U.S. patent application number 12/197614 was filed with the patent office on 2009-08-20 for spg stimulation for enhancing neurogenesis and brain metabolism.
This patent application is currently assigned to BRAINSGATE LTD.. Invention is credited to Hernan Altman, Gal Ariav, Avinoam Dayan, Yoram Solberg.
Application Number | 20090210026 12/197614 |
Document ID | / |
Family ID | 40955821 |
Filed Date | 2009-08-20 |
United States Patent
Application |
20090210026 |
Kind Code |
A1 |
Solberg; Yoram ; et
al. |
August 20, 2009 |
SPG STIMULATION FOR ENHANCING NEUROGENESIS AND BRAIN METABOLISM
Abstract
A method is provided, including identifying an electrical
stimulation protocol as being suitable for augmenting genesis of
one or more cell populations in at least one brain region of the
subject. The cell genesis is augmented by applying the identified
stimulation protocol to an SPG, a greater palatine nerve, a branch
of the greater palatine nerve, a lesser palatine nerve, a
sphenopalatine nerve, a communicating branch between a maxillary
nerve and an SPG, an otic ganglion, an afferent fiber going into
the otic ganglion, an efferent fiber going out of the otic
ganglion, an infraorbital nerve, a vidian nerve, a greater
superficial petrosal nerve, a lesser deep petrosal nerve, a
maxillary nerve, a branch of the maxillary nerve, a nasopalatine
nerve, a peripheral site that provides direct or indirect afferent
innervation to the SPG, or a peripheral site that is directly or
indirectly efferently innervated by the SPG.
Inventors: |
Solberg; Yoram; (Herzeliya,
IL) ; Ariav; Gal; (Givaat-Ada, IL) ; Altman;
Hernan; (Haifa, IL) ; Dayan; Avinoam; (Zikron
Yaakov, IL) |
Correspondence
Address: |
RATNERPRESTIA
P.O. BOX 980
VALLEY FORGE
PA
19482
US
|
Assignee: |
BRAINSGATE LTD.
Caesarea
IL
|
Family ID: |
40955821 |
Appl. No.: |
12/197614 |
Filed: |
August 25, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11465381 |
Aug 17, 2006 |
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12197614 |
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60966613 |
Aug 28, 2007 |
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60966614 |
Aug 28, 2007 |
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Current U.S.
Class: |
607/45 |
Current CPC
Class: |
A61N 1/3787 20130101;
A61N 1/36017 20130101; A61N 1/36082 20130101 |
Class at
Publication: |
607/45 |
International
Class: |
A61N 1/36 20060101
A61N001/36 |
Claims
1. A method comprising: identifying an electrical stimulation
protocol as being suitable for augmenting genesis of one or more
cell populations in at least one brain region of the subject; and
augmenting the cell genesis by applying the identified stimulation
protocol to a site of the subject selected from the group
consisting of: a sphenopalatine ganglion (SPG), a greater palatine
nerve, a branch of the greater palatine nerve, a lesser palatine
nerve, a sphenopalatine nerve, a communicating branch between a
maxillary nerve and an SPG, an otic ganglion, an afferent fiber
going into the otic ganglion, an efferent fiber going out of the
otic ganglion, an infraorbital nerve, a vidian nerve, a greater
superficial petrosal nerve, a lesser deep petrosal nerve, a
maxillary nerve, a branch of the maxillary nerve, a nasopalatine
nerve, a peripheral site that provides direct or indirect afferent
innervation to the SPG, and a peripheral site that is directly or
indirectly efferently innervated by the SPG.
2. The method according to claim 1, wherein the site is selected
from the group consisting of: the SPG, the greater palatine nerve,
the lesser palatine nerve, the sphenopalatine nerve, the
communicating branch between the maxillary nerve and the SPG, the
otic ganglion, the afferent fiber going into the otic ganglion, the
efferent fiber going out of the otic ganglion, the infraorbital
nerve, the vidian nerve, the greater superficial petrosal nerve,
and the lesser deep petrosal nerve.
3. The method according to claim 1, wherein identifying the
stimulation protocol comprises identifying the stimulation protocol
as being suitable for augmenting neurogenesis in the at least one
brain region.
4. The method according to claim 1, wherein identifying the
stimulation protocol comprises identifying the stimulation protocol
as being suitable for augmenting angiogenesis in the at least one
brain region.
5. The method according to claim 1, wherein identifying the
stimulation protocol comprises identifying the stimulation protocol
as being suitable for augmenting glia-genesis in the at least one
brain region.
6. The method according to claim 1, and comprising identifying that
the subject suffers from an adverse cerebral condition, wherein
augmenting the cell genesis comprises augmenting the cell genesis
responsively to identifying that the subject suffers from the
adverse cerebral condition.
7. The method according to claim 6, wherein the cerebral condition
causes a brain area of the subject to be diseased, and wherein the
at least one brain region is selected from the group consisting of:
a vicinity of the diseased brain area, and a brain area other than
the vicinity of the diseased brain area.
8. The method according to claim 6, wherein identifying that the
subject suffers from the adverse cerebral condition comprises
identifying that the subject suffers from a cerebrovascular
infarction.
9. The method according to claim 8, wherein augmenting the cell
genesis comprising commencing applying the stimulation at least 18
hours after an occurrence of the infarction.
10. The method according to claim 1, and comprising identifying
that the subject may benefit from the augmented cell genesis,
wherein augmenting the cell genesis comprises augmenting the cell
genesis responsively to identifying that the subject may benefit
from the augmented cell genesis.
11. A method for treating a subject, comprising: identifying an
electrical stimulation protocol as being suitable for improving a
metabolic state of a brain area of a subject; and improving the
metabolic state by applying the stimulation protocol to a site of
the subject selected from the group consisting of: a sphenopalatine
ganglion (SPG), a greater palatine nerve, a branch of the greater
palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a
communicating branch between a maxillary nerve and an SPG, an otic
ganglion, an afferent fiber going into the otic ganglion, an
efferent fiber going out of the otic ganglion, an infraorbital
nerve, a vidian nerve, a greater superficial petrosal nerve, a
lesser deep petrosal nerve, a maxillary nerve, a branch of the
maxillary nerve, a nasopalatine nerve, a peripheral site that
provides direct or indirect afferent innervation to the SPG, and a
peripheral site that is directly or indirectly efferently
innervated by the SPG.
12. The method according to claim 11, wherein the site is selected
from the group consisting of: the SPG, the greater palatine nerve,
the lesser palatine nerve, the sphenopalatine nerve, the
communicating branch between the maxillary nerve and the SPG, the
otic ganglion, the afferent fiber going into the otic ganglion, the
efferent fiber going out of the otic ganglion, the infraorbital
nerve, the vidian nerve, the greater superficial petrosal nerve,
and the lesser deep petrosal nerve.
13. The method according to claim 11, wherein identifying the
stimulation protocol comprises identifying the stimulation protocol
as suitable for reducing a lactate concentration in the brain
area.
14. The method according to claim 11, and comprising identifying
that the subject suffers from an adverse cerebral condition,
wherein improving the metabolic state comprises improving the
metabolic state responsively to identifying that the subject
suffers from the adverse cerebral condition.
15. The method according to claim 14, wherein identifying that the
subject suffers from the adverse cerebral condition comprises
identifying that the subject suffers from a cerebrovascular
infarction.
16. The method according to claim 14, wherein improving the
metabolic state comprises commencing applying the stimulation at
least 18 hours after an occurrence of the infarction.
17. The method according to claim 14, wherein the brain area is an
ischemic core of the infarction.
18. The method according to claim 17, wherein identifying the
stimulation protocol comprises identifying the stimulation protocol
as suitable for reviving at least a portion of the ischemic
core.
19. The method according to claim 14, wherein the brain area is an
ischemic penumbra of the infarction.
20. The method according to claim 19, wherein identifying the
stimulation protocol comprises identifying the stimulation protocol
as suitable for reviving at least a portion of the ischemic
penumbra.
21. The method according to claim 11, and comprising identifying
that the subject may benefit from the improved metabolic state,
wherein improving the metabolic state comprises improving the
metabolic state responsively to identifying that the subject may
benefit from the improved metabolic state.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of U.S.
application Ser. No. 11/465,381, filed Aug. 17, 2006, which is
assigned to the assignee of the present application and is
incorporated herein by reference.
[0002] The present application claims the benefit of: (i) U.S.
Provisional Application 60/966,613, filed Aug. 28, 2007, and (ii)
U.S. Provisional Application 60/966,614, filed Aug. 28, 2007, both
of which are assigned to the assignee of the present application
and are incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The present invention relates generally to medical
procedures and devices. More specifically, the invention relates to
the use of stimulation for treating medical conditions of the
brain.
BACKGROUND OF THE INVENTION
[0004] Stimulation of the sphenopalatine ganglion (SPG) treats
various acute brain hypoperfusion states, such as occur during
acute ischemic stroke. During acute ischemic stroke, blood supply
to the brain is abruptly blocked by either a thrombus or an
embolus. As a result, the blood supply to a localized area of the
brain in the center of the infarction is substantially reduced to a
level that is insufficient to meet the tissue's metabolic needs for
oxygen and other nutrients. This reduction leads to rapid neuronal
cell death in this area within several minutes after the stroke.
The blood supply received by adjacent tissue, called the penumbra,
is insufficient to main the metabolism of this tissue, which thus
suffers from hypoxic conditions which leads to gradual neuronal
death within several hours after the stroke. Following stroke, new
neurons are generated, which migrate to the infarcted areas in an
attempt to restore the damaged tissue.
[0005] US Patent Application Publication 2007/0083245 to Lamensdorf
et al., which is incorporated herein by reference, describes
apparatus for treatment, including one or more electrodes,
configured to be applied to a site of a subject, and adverse
cerebrovascular condition treatment functionality. The
functionality comprises a control unit configured to drive the one
or more electrodes to apply electrical stimulation to the site
during a plurality of stimulation periods which includes at least
first and last stimulation periods, set an inter-period interval
between initiation of the first stimulation period and initiation
of the last stimulation period to be at least 24 hours, and
configure the stimulation during the first and last stimulation
periods to induce at least one neuroprotective occurrence selected
from the group consisting of: an increase in cerebral blood flow
(CBF) of the subject, and a release of one or more neuroprotective
substances. The site is selected from the group consisting of: a
sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser
palatine nerve, a sphenopalatine nerve, a communicating branch
between a maxillary nerve and an SPG, an otic ganglion, an afferent
fiber going into the otic ganglion, an efferent fiber going out of
the otic ganglion, an infraorbital nerve, a vidian nerve, a greater
superficial petrosal nerve, and a lesser deep petrosal nerve.
[0006] The '245 publication describes an in vivo experiment
assessing the effect of long-term rehabilitative SPG stimulation. A
rat tMCAO model of stroke was used to evaluate the benefits,
including neuromuscular, motility, cognitive, somatosensory,
somatomotor, infarct volume benefits, of rehabilitative SPG
stimulation using the techniques described therein. The stimulation
was applied for seven consecutive days beginning at 24 hours after
reperfusion in the tMCAO model. In summary, in the experiment, SPG
stimulation initiated 24 hours after tMCAO had advantageous results
for all five parameter groups evaluated. In addition, SPG
stimulation increased the number of neurons in all regions
counted.
[0007] PCT Publication WO 01/85094 and US Patent Application
Publications 2004/0015068 and 2004/0210269 to Shalev and Gross,
which are incorporated herein by reference, describe apparatus for
modifying a property of a brain of a patient, including electrodes
applied to a sphenopalatine ganglion (SPG) or a neural tract
originating in or leading to the SPG. A control unit drives the
electrodes to apply a current capable of inducing (a) an increase
in permeability of a blood-brain barrier (BBB) of the patient, (b)
a change in cerebral blood flow of the patient, and/or (c) an
inhibition of parasympathetic activity of the SPG.
[0008] U.S. Pat. No. 7,117,033 to Shalev et al., which is
incorporated herein by reference, describes a method for treating a
subject, including positioning at least one electrode at least one
site of the subject, such as the SPG, for less than about 3 hours,
applying an electrical current to the site of the subject, and
configuring the current to increase cerebral blood flow (CBF) of
the subject, so as to treat a condition of the subject.
[0009] PCT Publication WO 04/043218 to Gross et al., which is
incorporated herein by reference, describes apparatus for treating
a subject, including (a) a stimulation device, adapted to be
implanted in a vicinity of a site selected from the list consisting
of: a SPG and a neural tract originating in or leading to the SPG;
and (b) a connecting element, coupled to the stimulation device,
and adapted to be passed through at least a portion of a greater
palatine canal of the subject.
[0010] U.S. Pat. No. 6,526,318 to Ansarinia and related PCT
Publication WO 01/97905 to Ansarinia, which are incorporated herein
by reference, describe a method for the suppression or prevention
of various medical conditions, including pain, movement disorders,
autonomic disorders, and neuropsychiatric disorders. The method
includes positioning an electrode on or proximate to at least one
of the patient's SPG, sphenopalatine nerves, or vidian nerves, and
activating the electrode to apply an electrical signal to such
nerve. In a further embodiment for treating the same conditions,
the electrode used is activated to dispense a medication solution
or analgesic to such nerve.
[0011] The following patent application publications, all of which
are incorporated herein by reference, may be of interest: WO
03/090599, WO 04/010923, WO 04/043218, WO 04/044947, WO 04/045242,
WO 04/043217, WO 04/043334, WO 05/030025, WO 05/030118, US
2004/0220644, US 2006/0020299, and US 2005/0159790.
[0012] The following patents and patent application publications,
all of which are incorporated herein by reference, may be of
interest:
[0013] U.S. Pat. No. 6,853,858 to Shalev
[0014] U.S. Pat. No. 7,146,209 to Gross et al.
[0015] U.S. Pat. No. 5,752,515 to Jolesz et al.
[0016] U.S. Pat. No. 6,405,079 to Ansarinia
[0017] U.S. Pat. No. 6,432,986 to Levin
[0018] US Patent Application 2001/0004644 to Levin
[0019] Sun Y et al., in an article entitled, "Neuronal nitric oxide
synthase and ischemia-induced neurogenesis," J Cereb Blood Flow
Metab 25(4):485-92 (2005), which is incorporated herein by
reference, report that nitric oxide (NO) influences infarct size
after focal cerebral ischemia and also regulates neurogenesis in
the adult brain. These observations suggest that therapeutic
approaches to stroke that target NO signaling may provide
neuroprotection and also enhance brain repair through cell
replacement. In addition, ischemia itself stimulates neurogenesis,
and ischemia-induced neurogenesis may be regulated differently than
neurogenesis in nonischemic brain. Selective inhibition of neuronal
NO synthase may have the potential to both reduce infarct size and
enhance neurogenesis in stroke.
[0020] Wilner A, in an article entitled, "Who is at risk for
post-stroke dementia?" Neurology Reviews.com Vol. 11, No. 2
(February 2003), which is incorporated herein by reference,
describes the results of a study analyzing risk factors for
survival of a stroke and post-stroke dementia.
[0021] Hotta H et al., in an article entitled, "Effects of
stimulating the nucleus basalis of Meynert on blood flow and
delayed neuronal death following transient ischemia in rat cerebral
cortes," Jap J Phys 52:383-393 (2002), which is incorporated herein
by reference, report that stimulation of the nucleus basalis of
Meynert (NBM) in the rat was accompanied by vasodilatation and
increase in cortical blood flow. They suggest that NBM-originating
vasodilative activation can protect the ischemia-induced delayed
death of cortical neurons by preventing a blood flow decrease in
widespread cortices.
[0022] Reis D J et al., in an article entitled, "Electrical
stimulation of cerebellar fastigial nucleus reduces ischemic
infarction elicited by middle cerebral artery occlusion in rat," J
Cereb Blood Flow Metab 11(5):810-8 (1991), which is incorporated
herein by reference, report that electrical stimulation of the
cerebellar fastigial nucleus (FN) profoundly increases cerebral
blood flow via a cholinergic mechanism. Utilizing the rat middle
cerebral artery occlusion (MCAO) model, they demonstrated that one
hour of electrical stimulation of the FN has the capacity to
substantially reduce the infarct size at the rim of the cortex
dorsal and ventral to the infarction, and medially within the
thalamus and striatum corresponding to the penumbral zone. They
conclude that excitation of an intrinsic system in brain
represented in the rostral FN has the capacity to substantially
reduce an ischemic infarction.
[0023] Matsui T et al., in an article entitled, "The effects of
cervical spinal cord stimulation (cSCS) on experimental stroke,"
Pacing Clin Electrophysiol 12(4 Pt 2):726-32 (1989), which is
incorporated herein by reference, report that cSCS increases
regional cerebral blood flow, and, in a cat middle cerebral artery
occlusion model (MCAO), reduced the rate of death within 24 hours
after MCAO.
[0024] Segher O et al., in an article entitled, "Spinal cord
stimulation reducing infract volume in model of focal cerebral
ischemia in rats," J Neurosurg 99(1):131-137 (2003), which is
incorporated herein by reference, demonstrate that spinal cord
stimulation increases cerebral blood flow in rats and significantly
reduces stroke volume, suggesting that spinal cord stimulation
could be used for treatment and prevention of stroke.
[0025] The following references, which are incorporated herein by
reference, may be of interest: [0026] Henninger N et al.,
"Stimulating circle of Willis nerve fibers preserves the
diffusion-perfusion mismatch in experimental stroke," Stroke 2007;
38:2779-2786 [0027] Ayajiki K et al., "Effects of capsaicin and
nitric oxide synthase inhibitor on increase in cerebral blood flow
induced by sensory and parasympathetic nerve stimulation in the
rat," J Appl Physiol 2005; 98:1792-1798 [0028] Yarnitsky D et al.,
"Reversal of cerebral vasospasm by sphenopalatine ganglion
stimulation in a dog model of subarachnoid hemorrhage," Surg Neurol
2005; 64:5-11; discussion 11 [0029] Kano M et al., "Parasympathetic
denervation of rat pial vessels significantly increases infarction
volume following middle cerebral artery occlusion," J Cereb Blood
Flow Metab 1991; 11:628-637 [0030] Koketsu N et al., "Chronic
parasympathetic sectioning decreases regional cerebral blood flow
during hemorrhagic hypotension and increases infarct size after
middle cerebral artery occlusion in spontaneously hypertensive
rats," J Cereb Blood Flow Metab 1992; 12:613-620 [0031] Weber R et
al., "Present status of magnetic resonance imaging and spectroscopy
in animal stroke models," J Cereb Blood Flow Metab 2006; 26:591-604
[0032] Sager T N et al., "Changes in N-acetyl-aspartate content
during focal and global brain ischemia of the rat," J Cereb Blood
Flow Metab 1995; 15:639-646 [0033] Moffett J R et al.,
"N-acetylaspartate in the CNS: From neurodiagnostics to
neurobiology," Progress in Neurobiology 2007; 81:89-131 [0034]
Franke C et al., "Probability of metabolic tissue recovery after
thrombolytic treatment of experimental stroke: a magnetic resonance
spectroscopic imaging study in rat brain," J Cereb Blood Flow Metab
2000; 20:583-591 [0035] Demougeot C et al., "N-Acetylaspartate, a
marker of both cellular dysfunction and neuronal loss: its
relevance to studies of acute brain injury," J Neurochem 2001;
77:408-415. [0036] Demougeot C et al., "Reversible loss of
N-acetyl-aspartate in rats subjected to long-term focal cerebral
ischemia," J Cereb Blood Flow Metab 2003; 23:482-489. [0037] Meyer
J S et al., "Cognition and cerebral blood flow fluctuate together
in multi-infarct dementia," Stroke 1988; 19:163-169 [0038] Markus H
S et al., "Reduced cerebral blood flow in white matter in ischemic
leukoaraiosis demonstrated using quantitative exogenous contrast
based perfusion MRI," J Neurol Neurosurg Psychiatry 2000; 69:48-53
[0039] Kawamura J et al., "Leukoaraiosis correlates with cerebral
hypoperfusion in vascular dementia," Stroke 1991; 22:609-614 [0040]
Schmidt R et al., "White matter lesion progression, brain atrophy,
and cognitive decline: The Austrian Stroke Prevention Study," Ann
Neurol 2005; 58:610-616 [0041] Seylaz J et al., "Effects of
stimulation of the sphenopalatine ganglion on cortical blood flow
in the rat," Journal of Cerebral Blood Flow and Metabolism," 8,
875-878 (1988) [0042] Suzuki N et al., "Selective electrical
stimulation of postganglionic cerebrovascular parasympathetic nerve
fibers originating from the sphenopalatine ganglion enhances
cortical blood flow in the rat," Journal of Cerebral Blood Flow and
Metabolism, 10, 383-391 (1990) [0043] Branston N M, "The physiology
of the cerebrovascular parasympathetic innervation," British
Journal of Neurosurgery 9:319-329 (1995) [0044] Branston N M et
al., "Contribution of cerebrovascular parasympathetic and sensory
innervation to the short-term control of blood flow in rat cerebral
cortex," J Cereb Blood Flow Metab 15(3):525-31 (1995) [0045] Toda N
et al., "Cerebral vasodilation induced by stimulation of the
pterygopalatine ganglion and greater petrosal nerve in anesthetized
monkeys," Neuroscience 96(2):393-398 (2000) [0046] Seylaz J et al.,
"Effect of stimulation of the sphenopalatine ganglion on cortical
blood flow in the rat," J Cereb Blood Flow Metab 8(6):875-8 (1988)
[0047] Ziche M et al., "Nitric oxide and angiogenesis," J
Neurooncol 50:139-148 (2000) [0048] Kawamata T et al.,
"Intracisternal basic fibroblast growth factor (bFGF) enhances
behavioral recovery following focal cerebral infarction in the
rat," J Cereb Blood Flow Metab 16:542-547 (1996) [0049] Zhang F et
al., "Nitric oxide donors increase blood flow and reduce brain
damage in focal ischemia: evidence that nitric oxide is beneficial
in the early stages of cerebral ischemia," J Cereb Blood Flow Metab
14(2):217-26 (1994) [0050] Beridze M et al., "Effect of nitric
oxide initial blood levels on erythrocyte aggregability during 12
hours from ischemic stroke onset," Clin Hemorheol Microcirc
30(3-4):403-6 (2004) [0051] Phan T G et al., "Salvaging the
ischaemic penumbra: more than just reperfusion?" Clin Exp Pharmacol
Physiol 29(1-2):1-10 (2002) [0052] Zhang R et al., "Nitric oxide
enhances angiogenesis via the synthesis of vascular endothelial
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92(3):308-13 (2003) [0053] Zhang R et al., "A nitric oxide donor
induces neurogenesis and reduces functional deficits after stroke
in rats," Ann Neurol 50:602-611 (2001) [0054] Ziche M et al.,
"Nitric oxide and angiogenesis," J Neurooncol 50:139-148 (2000)
[0055] de la Torre J C, "Vascular basis of Alzheimer's
pathogenesis," Ann NY Acad Sci 977:196-215 (2002) [0056] Sandgren K
et al., "Vasoactive intestinal peptide and nitric oxide promote
survival of adult rat myenteric neurons in culture," J Neurosci Res
72(5):595-602 (2003) [0057] Khan M et al., "S-Nitrosoglutathione
reduces inflammation and protects brain against focal cerebral
ischemia in a rat model of experimental stroke," J Cereb Blood Flow
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SUMMARY OF THE INVENTION
[0059] In some embodiments of the present invention, excitatory
electrical stimulation is applied to the sphenopalatine ganglion
(SPG) to augment neurogenesis in a subject suffering from an
adverse cerebral condition, such as cerebral infarction, in order
to improve recovery from the condition. The inventors hypothesize
that such stimulation may augment the neurogenesis by increasing
blood perfusion to the damaged tissue, which improves the supply of
oxygen and other nutrients to the tissue, and/or by causing the
release of neurotransmitters and/or neuromodulators from SPG nerve
fibers. Alternatively, the stimulation is applied to another
"modulation target site" (MTS), as defined hereinbelow.
[0060] To evaluate the level of augmentation of neurogenesis in
infarcted rat brains caused by SPG stimulation, the inventors
conducted an experiment using a rat middle cerebral artery
occlusion (MCAO) model of stroke. Stroke was induced in two rats,
one of which served as a control, and the other of which was
treated with SPG stimulation beginning 24 hours after stroke. The
rats were sacrificed, and histopathological examinations and
immunohistochemical analysis for markers of newly born cells were
performed. The examinations indicated that the SPG-stimulated rat
had substantially more newly born cells than the control rat, and
that a substantially greater percentage of the newly born cells
were neuroblasts (the progenitor cells of neurons) in the
SPG-stimulated rat than in the control rat.
[0061] In some embodiments of the present invention, stimulation of
the SPG or another MTS augments neurogenesis in an infarcted brain,
thereby leading to a better prognosis for acute stroke patients.
Alternatively, such stimulation augments cell genesis
(neurogenesis, angiogenesis, and/or glia-genesis) in a brain
suffering from another adverse cerebral condition, such as chronic
cerebral hypoperfusion states (such as occur in vascular dementia
and Alzheimer's disease), neurodegenerative disorders (such as
Parkinson's disease) and electrical hyper-activity states (such as
epilepsy).
[0062] In some embodiments of the present invention, a method is
provided that comprises identifying that a subject may benefit from
augmented neurogenesis, and, responsively to the identifying,
applying stimulation to the SPG or another MTS of the subject.
Alternatively or additionally, the method comprises identifying a
stimulation protocol as suitable for augmenting neurogenesis, and
applying the identified protocol to a subject who may benefit from
augmented neurogenesis.
[0063] In some embodiments of the present invention, a method is
provided for augmenting neurogenesis in a subject who has not been
diagnosed with any neurological condition associated with reduced
neurogenesis or an elevated level of brain cell death. The method
comprises identifying that the subject may benefit from augmented
neurogenesis, and, responsively to identifying, applying chronic,
long-term stimulation to an MTS, such as the SPG. The chronic
stimulation has a duration of at least two weeks, at least four
weeks, at least three months, at least six months, or the remaining
life of the subject. During this chronic treatment, stimulation is
typically applied intermittently, such as during one session per
day, or less frequently, such as depending on the severity of
assessed risk. Alternatively, the stimulation is applied generally
constantly, typically at a low strength.
[0064] For some applications, identifying that the subject may
benefit from augmented neurogenesis comprises identifying that the
subject is at least a threshold age. For example, the threshold age
may be between about 50 and about 80 years. Alternatively or
additionally, the subject may identified because the subject
suffers from one or more symptoms of a vascular disorder, such as
hypertension, peripheral vascular disease, or coronary artery
disease. Alternatively or additionally, the method comprises
identifying that the subject suffers from reduced cardiac output,
e.g., caused by heart failure. Further alternatively or
additionally, the subject may be identified as potentially
benefiting from augmented neurogenesis if the subject has a family
history of any type of dementia, and/or the subject has
radiological findings suggestive of cerebral vascular disease or
Alzheimer's disease.
[0065] The stimulation is typically applied on a chronic, long-term
basis, i.e., for at least one week, such as at least two weeks, at
least four weeks, at least three months, at least six months, or
during the remaining life of the subject. During this chronic
treatment, stimulation is typically applied intermittently, such as
during one session per day, or less frequently, such as depending
on the severity of assessed risk. Alternatively, the stimulation is
applied generally constantly, typically at a low strength. For some
applications, the stimulation is applied bilaterally to both SPGs,
while for other applications, the stimulation is applied
unilaterally, such as to the MTS (e.g., the SPG) that supplies the
more affected hemisphere of the brain.
[0066] In some embodiments of the present invention, excitatory
electrical stimulation is applied to the SPG or another MTS of a
subject who suffers from an adverse cerebral condition, in order to
improve a metabolic state of a brain area affected by the adverse
cerebral condition, thereby improving recovery from the condition.
For some applications, the adverse cerebral condition is a
cerebrovascular infarction, and the stimulation augments the
recovery of the metabolic state of the brain area in the infarction
or a vicinity of the infarction. The inventors hypothesize that
such stimulation may improve the metabolic state by increasing
blood perfusion to the damaged tissue, which improves the supply of
oxygen and other nutrients to the tissue, and/or increases washout
or otherwise reduces concentrations of toxic waste products from
the damaged tissue. For example, lactate is a toxic waste product
which, in high concentrations, leads to acidosis of the tissue.
[0067] The inventors conducted an experiment to assess the ability
of SPG stimulation to augment stroke recovery in MCAO rats. Stroke
was induced in twenty rats, of which 7 served as a control group,
and of which 6 rats were treated with SPG stimulation beginning
18.+-.2 h after stroke. Longitudinal .sup.1H magnetic resonance
spectroscopic imaging (.sup.1HMRSI) and diffusion MRI (DWI) were
used to evaluate ischemic brain condition of the stimulated and
control rats at 16.+-.2 hours, 8 days, and 28 days after stroke.
The inventors found that levels of N-Acetyl-Aspartate (NAA), which
is considered to be a marker for neuronal density and viability
levels, in the stimulated and control rats were the same 16.+-.2
hours after stroke. 28 days after stroke, NAA levels were
significantly higher in the stimulated group compared to the
control group. This effect was more pronounced for regions with low
baseline NAA values. In addition, a damage index, calculated based
on DWI, showed significant deterioration for the controls which was
not observed for the stimulated animals.
[0068] In some embodiments of the present invention, electrical
stimulation of the SPG or another MTS reduces lactate concentration
in the acute phase of a cerebrovascular infarction, or during
another adverse cerebral condition. Such a reduction in lactate
concentration results in a better metabolic state for the surviving
cells. Preliminary experimental results in a rat model indicate the
SPG stimulation reduces such lactate concentration in the acute
phase of the infarction.
[0069] In some embodiments of the present invention, stimulation of
the SPG or another MTS augments the recovery of the metabolic state
of an infarcted brain area, which leads to a better prognosis for
acute stroke patients. Alternatively, such stimulation augments the
recovery of the metabolic state of a brain area affected by another
adverse cerebral condition, such as chronic cerebral hypoperfusion
states (such as occur in vascular dementia and Alzheimer's
disease), neurodegenerative disorders (such as Parkinson's
disease), and electrical hyperactivity states (such as epilepsy
where there is a higher metabolic demand in the affected brain
areas).
[0070] In some embodiments of the present invention, a method is
provided for improving a metabolic state of the brain in a subject
who has not been diagnosed with any neurological condition
associated with a reduced level of brain metabolism. The method
comprises identifying that the subject may benefit from an improved
metabolic state, and, responsively to identifying, applying
chronic, long-term stimulation to an MTS, such as the SPG. The
chronic stimulation has a duration of at least two weeks, at least
four weeks, at least three months, at least six months, or the
remaining life of the subject. During this chronic treatment,
stimulation is typically applied intermittently, such as during one
session per day, or less frequently, such as depending on the
severity of assessed risk. Alternatively, the stimulation is
applied generally constantly, typically at a low strength.
[0071] The stimulation is typically applied on a chronic, long-term
basis, i.e., for at least one week, such as at least two weeks, at
least four weeks, at least three months, at least six months, or
during the remaining life of the subject. During this chronic
treatment, stimulation is typically applied intermittently, such as
during one session per day, or less frequently, such as depending
on the severity of assessed risk. Alternatively, the stimulation is
applied generally constantly, typically at a low strength. For some
applications, the stimulation is applied bilaterally to both SPGs,
while for other applications, the stimulation is applied
unilaterally, such as to the MTS (e.g., the SPG) that supplies the
more affected hemisphere of the brain.
[0072] In the present patent application, a "modulation target
site" (MTS) consists of: [0073] an SPG (also called a
pterygopalatine ganglion); [0074] a nerve of the pterygoid canal
(also called a vidian nerve), such as a greater superficial
petrosal nerve (a preganglionic parasympathetic nerve) or a lesser
deep petrosal nerve (a postganglionic sympathetic nerve); [0075] a
greater palatine nerve; [0076] a branch of the greater palatine
nerve [0077] a lesser palatine nerve; [0078] a sphenopalatine
nerve; [0079] a communicating branch between the maxillary nerve
and the sphenopalatine ganglion; [0080] an otic ganglion; [0081] an
afferent fiber going into the otic ganglion; [0082] an efferent
fiber going out of the otic ganglion; [0083] an infraorbital nerve;
[0084] a maxillary nerve; [0085] a branch of the maxillary nerve;
[0086] a nasopalatine nerve; [0087] a peripheral (i.e., non-brain)
site that provides direct or indirect afferent innervation to the
SPG; or [0088] a peripheral site that is directly or indirectly
efferently innervated by the SPG (which causes retrograde
activation of efferent nerve fibers, thereby stimulating the
SPG).
[0089] For example, such peripheral sites may include mucosa of the
nose or nasal pharynx, mucosa of the hard and soft palate,
conjunctiva of the eye, and the lacrimal gland.
[0090] It is to be appreciated that references herein to specific
modulation target sites are to be understood as including other
modulation target sites, as appropriate.
[0091] It is further to be appreciated that insertion and
modulation sites, methods of insertion and/or implantation, and
parameters of modulation are described herein by way of
illustration and not limitation, and that the scope of the present
invention includes other possibilities which would be obvious to
someone of ordinary skill in the art who has read the present
patent application.
[0092] It is yet further to be appreciated that while some
embodiments of the invention are generally described herein with
respect to electrical transmission of power and electrical
modulation of tissue, other modes of energy transport may be used
as well. Such energy includes, but is not limited to, direct or
induced electromagnetic energy, radiofrequency (RF) transmission,
mechanical vibration, ultrasonic transmission, optical power, and
low power laser energy (via, for example, a fiber optic cable).
[0093] It is additionally to be appreciated that whereas some
embodiments of the present invention are described with respect to
application of electrical currents to tissue, this is to be
understood in the context of the present patent application and in
the claims as being substantially equivalent to applying an
electrical field, e.g., by creating a voltage drop between two
electrodes.
[0094] In embodiments of the present invention, treating an adverse
brain event or condition typically includes identifying that a
subject is suffering from, and/or has suffered from, the brain
event or condition.
[0095] There is therefore provided, in accordance with an
embodiment of the present invention, a method including:
[0096] identifying an electrical stimulation protocol as being
suitable for augmenting genesis of one or more cell populations in
at least one brain region of the subject; and
[0097] augmenting the cell genesis by applying the identified
stimulation protocol to a site of the subject selected from the
group consisting of: a sphenopalatine ganglion (SPG), a greater
palatine nerve, a branch of the greater palatine nerve, a lesser
palatine nerve, a sphenopalatine nerve, a communicating branch
between a maxillary nerve and an SPG, an otic ganglion, an afferent
fiber going into the otic ganglion, an efferent fiber going out of
the otic ganglion, an infraorbital nerve, a vidian nerve, a greater
superficial petrosal nerve, a lesser deep petrosal nerve, a
maxillary nerve, a branch of the maxillary nerve, a nasopalatine
nerve, a peripheral site that provides direct or indirect afferent
innervation to the SPG, and a peripheral site that is directly or
indirectly efferently innervated by the SPG.
[0098] For some applications, the site is selected from the group
consisting of: the SPG, the greater palatine nerve, the lesser
palatine nerve, the sphenopalatine nerve, the communicating branch
between the maxillary nerve and the SPG, the otic ganglion, the
afferent fiber going into the otic ganglion, the efferent fiber
going out of the otic ganglion, the infraorbital nerve, the vidian
nerve, the greater superficial petrosal nerve, and the lesser deep
petrosal nerve.
[0099] For some applications, identifying the stimulation protocol
includes identifying the stimulation protocol as being suitable for
augmenting neurogenesis in the at least one brain region.
Alternatively or additionally, identifying the stimulation protocol
includes identifying the stimulation protocol as being suitable for
augmenting angiogenesis in the at least one brain region. Further
alternatively or additionally, identifying the stimulation protocol
includes identifying the stimulation protocol as being suitable for
augmenting glia-genesis in the at least one brain region.
[0100] In an embodiment, the method includes identifying that the
subject suffers from an adverse cerebral condition, and augmenting
the cell genesis includes augmenting the cell genesis responsively
to identifying that the subject suffers from the adverse cerebral
condition. For some applications, the cerebral condition causes a
brain area of the subject to be diseased, and the at least one
brain region is selected from the group consisting of: a vicinity
of the diseased brain area, and a brain area other than the
vicinity of the diseased brain area. For some applications,
identifying that the subject suffers from the adverse cerebral
condition includes identifying that the subject suffers from a
cerebrovascular infarction. Augmenting the cell genesis may include
commencing applying the stimulation at least 18 hours after an
occurrence of the infarction.
[0101] Typically, the method includes identifying that the subject
may benefit from the augmented cell genesis, and augmenting the
cell genesis includes augmenting the cell genesis responsively to
identifying that the subject may benefit from the augmented cell
genesis.
[0102] There is further provided, in accordance with an embodiment
of the present invention, a method for treating a subject,
including:
[0103] identifying an electrical stimulation protocol as being
suitable for improving a metabolic state of a brain area of a
subject; and
[0104] improving the metabolic state by applying the stimulation
protocol to a site of the subject selected from the group
consisting of: a sphenopalatine ganglion (SPG), a greater palatine
nerve, a branch of the greater palatine nerve, a lesser palatine
nerve, a sphenopalatine nerve, a communicating branch between a
maxillary nerve and an SPG, an otic ganglion, an afferent fiber
going into the otic ganglion, an efferent fiber going out of the
otic ganglion, an infraorbital nerve, a vidian nerve, a greater
superficial petrosal nerve, a lesser deep petrosal nerve, a
maxillary nerve, a branch of the maxillary nerve, a nasopalatine
nerve, a peripheral site that provides direct or indirect afferent
innervation to the SPG, and a peripheral site that is directly or
indirectly efferently innervated by the SPG.
[0105] For some applications, the site is selected from the group
consisting of: the SPG, the greater palatine nerve, the lesser
palatine nerve, the sphenopalatine nerve, the communicating branch
between the maxillary nerve and the SPG, the otic ganglion, the
afferent fiber going into the otic ganglion, the efferent fiber
going out of the otic ganglion, the infraorbital nerve, the vidian
nerve, the greater superficial petrosal nerve, and the lesser deep
petrosal nerve.
[0106] In an embodiment, identifying the stimulation protocol
includes identifying the stimulation protocol as suitable for
reducing a lactate concentration in the brain area.
[0107] For some applications, the method includes identifying that
the subject suffers from an adverse cerebral condition, and
improving the metabolic state includes improving the metabolic
state responsively to identifying that the subject suffers from the
adverse cerebral condition. For some applications, identifying that
the subject suffers from the adverse cerebral condition includes
identifying that the subject suffers from a cerebrovascular
infarction. For some applications, improving the metabolic state
includes commencing applying the stimulation at least 18 hours
after an occurrence of the infarction. For some applications, the
brain area is an ischemic core of the infarction. Identifying the
stimulation protocol may include identifying the stimulation
protocol as suitable for reviving at least a portion of the
ischemic core. For some applications, the brain area is an ischemic
penumbra of the infarction. Identifying the stimulation protocol
may include identifying the stimulation protocol as suitable for
reviving at least a portion of the ischemic penumbra.
[0108] Typically, the method includes identifying that the subject
may benefit from the improved metabolic state, and improving the
metabolic state includes improving the metabolic state responsively
to identifying that the subject may benefit from the improved
metabolic state.
[0109] The present invention will be more fully understood from the
following detailed description of the embodiments thereof, taken
together with the drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0110] FIG. 1 is a schematic illustration of a neural stimulation
system, in accordance with an embodiment of the present
invention;
[0111] FIGS. 2A-H are graphs showing results of an in vivo
experiment assessing the effect of long-term rehabilitative SPG
stimulation, measured in accordance with an embodiment of the
present invention;
[0112] FIG. 3 is a graph showing changes in total normalized
N-Acetyl-Aspartate (NAA) values at three experimental time points
post-t-MCAO during a rat experiment performed in accordance with an
embodiment of the present invention;
[0113] FIGS. 4A-C are graphs showing changes in NAA levels in
respective brain areas categorized according to initial normalized
NAA values measured in the experiment of FIG. 3;
[0114] FIG. 5 is a graph showing a damage index measured in the
experiment of FIG. 3;
[0115] FIG. 6 is a graph showing average modified Neuro Severity
Scores (mNSS) measured in the experiment of FIG. 3; and
[0116] FIGS. 7A-B and 8A-B show magnetic resonance spectra obtained
during an experiment conducted by the inventors, measured in
accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF EMBODIMENTS
[0117] FIG. 1 is a schematic illustration of a neural stimulation
system 20, in accordance with an embodiment of the present
invention. System 20 typically comprises an implantable neural
stimulator 30, an external control unit 32, and, for some
applications, an external driver 34. Stimulator 30 comprises an
elongated support element 36, one or more electrodes 38 fixed to
the support element in a vicinity of a distal end thereof, and
circuitry 40 coupled to the support element in a vicinity of a
proximal end thereof. Circuitry 40 typically comprises a wireless
coupling element (which typically comprises a coil, and additional
elements, such as one or more rectifiers, capacitors, amplifiers,
or filters. One or more leads (not shown in FIG. 1), which pass
along, through, or around support element 36, couple electrodes 38
to circuitry 40. Alternatively, the leads function as the support
element, i.e., the support element does not comprise any structural
elements in addition to the leads. Circuitry 40 is shown
schematically in FIG. 1; the circuitry may employ one or more of
the more detailed configurations described with reference to FIGS.
3A-B, 4A-B, and 5A-D of U.S. patent application Ser. No.
11/349,020, filed Feb. 7, 2006, which published as US Patent
Application Publication 2006/0287677, and which is incorporated
herein by reference.
[0118] Stimulator 30 is configured to be passed through a greater
palatine foramen 42 of a hard palate 50 of an oral cavity 52 of a
subject into a greater palatine canal 54, such that electrodes 38
are brought into a vicinity of a sphenopalatine ganglion (SPG) 56.
For some applications, the entire stimulator is contained within
greater palatine canal 54, while for other applications, at least a
portion of the circuitry and/or the support element are positioned
submucosally in the oral cavity. For clarity of illustration, the
greater and lesser palatine nerves, and the greater and less
palatine arteries are not shown in the figures. During an
implantation procedure, stimulator 30 is typically passed through
greater palatine foramen 42 posterior to the greater palatine nerve
and artery, which are manipulated into an anterior position within
the canal.
[0119] For some applications, electrodes 38 apply a monophasic
waveform to SPG 56, while for other applications, electrodes 38
apply a biphasic waveform. Alternatively or additionally, waveforms
and/or stimulation techniques may be used that are described in one
or more of the patent applications incorporated by reference
hereinbelow, or waveforms and/or stimulation techniques may be used
that are known in the art of neural stimulation.
[0120] Circuitry 40 of stimulator 30 comprises a stimulator
wireless coupling element, which typically comprises at least one
coil. For applications in which system 20 comprises external driver
34, the external driver is configured to transmit power, typically
using RF energy, to stimulator via a driver wireless coupling
element and the stimulator wireless coupling element, for powering
stimulator 30, and to transmit and/or receive data to/from the
stimulator via the wireless coupling element. Driver 34 is
typically configured to be worn by the subject, such as by being
coupled to a headset (such as a cellular phone headset) or a
necklace, or coupled to an ear of the subject. Driver 34 typically
uses the driver wireless coupling element, or a separate wireless
coupling element, to wirelessly relay data to and receive data from
external control unit 32. For example, such data may be transmitted
using the Bluetooth protocol or another wireless communication
protocol, or using an infrared signal. Alternatively, driver 34 is
coupled to external control unit 32 by one or more wires.
[0121] For other applications in which system 20 does not comprise
external driver 34, the functionality and components of driver 34
are incorporated into external control 34 unit, which transmits
power to and sends and/or receives data to/from circuitry 40. In
these applications, external control unit 32 is typically
configured to be worn by the subject, such as by being coupled to a
headset (such as a cellular phone headset) or a necklace, or
coupled to an ear of the subject.
[0122] Whether transmitted by the external driver or directly by
the control unit, such data typically includes stimulation control
signals, parameters, and/or feedback information. Such data is
typically transmitted only periodically, rather than constantly
during stimulation. Circuitry 40 of stimulator 30 is configured to
generate the stimulation waveform applied by electrodes 38, based
on the configured parameters. For some applications, driver 34 or
external control unit 32 combines the data and the energy into a
single signal, such as by modulating the data onto the carrier
frequency of the transmitted energy, in which the stimulator
demodulates the received signal to obtain the data. Alternatively,
the data and the energy are transmitted in separate signals.
[0123] Although electrodes 38 have been described as being applied
to an SPG of the subject, for some applications the electrodes are
applied to another MTS of the subject, as defined hereinabove. For
some of these applications, electrodes 38 are passed through the
greater palatine canal to the MTS, while for other applications the
electrodes are passed through only a portion of the greater
palatine canal, or are advanced to the MTS by another route.
[0124] For some applications, system 20 applies excitatory
electrical stimulation to the SPG or another MTS using the
following parameters: [0125] amplitude: 0.5-10 mA [0126] frequency:
10-30 Hz [0127] pulse width: 100-500 .mu.sec [0128] cycles: 1-10
cycles per hour [0129] cycle on/off time: 60 seconds/12 seconds, 4
seconds/15 seconds, or 30 seconds/60 seconds
[0130] For some applications, system 20 provides stimulation by
applying a plurality of cycles of stimulation, each cycle including
an "on" period (e.g., between 2 and 90 seconds) followed by an
"off" period (e.g., between 8 and 90 seconds). Such cycles are
applied a certain number of times per hour, typically spaced evenly
throughout the hour. For example, if the cycles are applied four
times per hour, the four cycles may be applied at the beginning of
the hour, 15 minutes into the hour, 30 minutes into the hour, and
45 minutes into the hour, respectively. For some applications, each
stimulation is applied in sets of two or more cycles. For example,
if the stimulation is applied four times per hour, a set of two
cycles may be applied at the beginning of the hour, 15 minutes into
the hour, 30 minutes into the hour, and 45 minutes into the hour,
respectively.
[0131] Alternatively or additionally, system 20 is configured with
parameters used in the experiments described hereinbelow with
reference to Tables 1 and 2 and FIGS. 2-8B.
[0132] As appropriate, placement of stimulator 30 may be
facilitated by fluoroscopy, x-ray guidance, fine endoscopic surgery
(FES) techniques or by any other effective guidance method known in
the art, or by combinations of the aforementioned. Typically, skin
temperature and/or cerebral blood flow (CBF) is measured
concurrently with insertion. CBF may be measured with, for example,
a laser Doppler unit positioned at the patient's forehead or
transcranial Doppler measurements. Verification of proper
implantation of the electrodes onto the appropriate neural
structure may be performed by activating the device, and generally
simultaneously monitoring CBF. For some applications, stimulator 30
is implanted using techniques described in U.S. patent application
Ser. No. 10/535,024, filed Dec. 27, 2005, entitled, "Surgical tools
and techniques for stimulation," which is assigned to the assignee
of the present application and is incorporated herein by reference,
and/or in the above-mentioned PCT Publication WO 04/043218. For
some applications, techniques described herein are performed in
combination with apparatus and/or methods that are described in
above-mentioned U.S. patent application Ser. No. 11/349,020.
Augmentation of Cell Genesis
[0133] In an embodiment of the present invention, system 20 is used
to apply excitatory electrical stimulation to the SPG or another
MTS to augment genesis of one or more cell populations in at least
one brain region of a subject suffering from an adverse cerebral
condition, such as cerebral infarction, in order to improve
recovery from the condition. The inventors hypothesize that such
stimulation may augment the neurogenesis by increasing blood
perfusion to the damaged tissue, which improves the supply of
oxygen and other nutrients to the tissue, and/or by causing the
release of neurotransmitters and/or neuromodulators from the SPG
nerve fibers.
[0134] A method for applying such stimulation comprises identifying
an electrical stimulation protocol as being suitable for augmenting
genesis of one or more cell populations in the at least one brain
region of the subject, and augmenting the cell genesis by applying
the identified stimulation protocol to the SPG or another MTS. For
some applications, the stimulation protocol is identified as being
suitable for augmenting neurogenesis in the at least one brain
region. Alternatively or additionally, the stimulation protocol is
identified as being suitable for augmenting angiogenesis in the at
least one brain region. Further alternatively or additionally, the
stimulation protocol is identified as being suitable for augmenting
glia-genesis in the at least one brain region. Typically, the
method comprises identifying that the subject may benefit from the
augmented cell genesis, and augmenting the cell genesis comprises
augmenting the cell genesis responsively to identifying that the
subject may benefit from the augmented cell genesis.
[0135] In the present patent application, including in the claims,
augmenting cell genesis means causing an increase in a level of
cell genesis compared to the cell genesis that would naturally
occur if the stimulation were not applied. As mentioned above, Sun
Y et al. report that ischemia itself stimulates neurogenesis. The
techniques of some embodiments of the present invention cause a
greater level of neurogenesis than the ischemia would stimulate in
the absence of the electrical stimulation of the SPG or another
MTS.
[0136] In an embodiment of the present invention, the method
comprises identifying that the subject suffers from an adverse
cerebral condition, and the cell genesis is augmented responsively
to identifying that the subject suffers from the adverse cerebral
condition. The cerebral condition causes a brain area of the
subject to be diseased. For some applications, the stimulation
causes cell genesis in a vicinity of the diseased brain area.
Alternatively or additionally, the stimulation causes cell genesis
in a brain area other than the vicinity of the diseased brain area.
For some applications, the adverse cerebral condition is a
cerebrovascular infarction (stroke), and the augmentation of cell
genesis leads to a better prognosis for acute stroke patients.
Alternatively, such stimulation augments neurogenesis in a brain
suffering from another adverse cerebral condition, such as chronic
cerebral hypoperfusion states (such as occur in vascular dementia
and Alzheimer's disease), neurodegenerative disorders (such as
Parkinson's disease) and electrical hyper-activity states (such as
epilepsy).
[0137] In an embodiment of the present invention, application of
the stimulation commences at least 18 hours after an occurrence of
a cerebrovascular infarction. Experimental evidence described
hereinbelow with reference to Table 1 supports the efficacy of
stimulation commencing 24 hours after stroke.
[0138] In some embodiments of the present invention, a method is
provided that comprises identifying that a subject may benefit from
augmented neurogenesis, and, responsively to the identifying,
applying stimulation to the SPG or another MTS of the subject.
Alternatively or additionally, the method comprises identifying a
stimulation protocol as suitable for augmenting neurogenesis, and
applying the identified protocol to a subject who may benefit from
augmented neurogenesis.
[0139] In some embodiments of the present invention, a method is
provided for augmenting neurogenesis in a subject who has not been
diagnosed with any neurological condition associated with reduced
neurogenesis or an elevated level of brain cell death. The method
comprises identifying that the subject may benefit from augmented
neurogenesis, and, responsively to identifying, applying chronic,
long-term stimulation to an MTS, such as the SPG. The chronic
stimulation has a duration of at least two weeks, at least four
weeks, at least three months, at least six months, or the remaining
life of the subject. During this chronic treatment, stimulation is
typically applied intermittently, such as during one session per
day, or less frequently, such as depending on the severity of
assessed risk. Alternatively, the stimulation is applied generally
constantly, typically at a low strength.
[0140] For some applications, identifying that the subject may
benefit from augmented neurogenesis comprises identifying that the
subject is at least a threshold age. For example, the threshold age
may be between about 50 and about 80 years. Alternatively or
additionally, the subject may identified because the subject
suffers from one or more symptoms of a vascular disorder, such as
hypertension, peripheral vascular disease, or coronary artery
disease. Alternatively or additionally, the method comprises
identifying that the subject suffers from reduced cardiac output,
e.g., caused by heart failure. Further alternatively or
additionally, the subject may be identified as potentially
benefiting from augmented neurogenesis if the subject has a family
history of any type of dementia, and/or the subject has
radiological findings suggestive of cerebral vascular disease or
Alzheimer's disease.
Neurogenesis Experimental Results
[0141] The inventors conducted an experiment to evaluate the level
of augmentation of neurogenesis in infarcted rat brains caused by
SPG stimulation. The experiment used a rat middle cerebral artery
occlusion (MCAO) model of stroke. Stroke was induced in two rats,
one of which served as a control, and the other of which rat was
treated with SPG stimulation beginning 24 hours after stroke. The
rats were sacrificed, and histopathological examinations and
immunohistochemical analysis for markers of newly born cells were
performed.
[0142] The following table shows cell counts in tissue taken from
the proliferating zone of the brain (where new cells are generated
in the brain):
TABLE-US-00001 TABLE 1 Number of DCX- Ki-67- Cells both
DCX-positive positive cells positive cells and Ki-67-positive (%
total cells) (% total cells) (% total cells) Control 128.3 .+-.
49.3 17.25 .+-. 12.23 8.75 .+-. 2.29 rat (55.1 .+-. 17.1) (9.3 .+-.
3.8) (4.5 .+-. 1.3) Stimulated 56.7 .+-. 27.7 32.33 .+-. 3.38 16.6
.+-. 2.3 rat (47.7 .+-. 4.3) (41.0 .+-. 14.9) (19.5 .+-. 7.2)
[0143] (The ranges of values represent data measured in several
slices taken from each rat brain.)
[0144] The doublecortin (DCX) protein is a marker for immature
neurons, and is thus a marker for neurogenesis. The Ki-67 protein
is a cellular marker for proliferation.
[0145] As can be seen in Table 1, a substantially greater
percentage of the cells in the proliferating zone are newly born
cells in the stimulated rat than in the control rat (41% vs. 9.3%),
as indicated by the Ki-67 marker. Furthermore, a greater percentage
of the newly born cells were neurons (positive for both the DCX and
Ki-67 markers) in the stimulated rat and control rat (19.5% vs.
4.5%).
[0146] The examinations indicated that the SPG-stimulated rat had
substantially more newly born cells than the control rat, and that
a substantially greater percentage of the newly born cells were
neuroblasts (the progenitor cells of neurons) in the SPG-stimulated
rat than in the control rat.
[0147] Reference is made to FIGS. 2A-H, which are graphs showing
results of an in vivo experiment assessing the effect of long-term
rehabilitative SPG stimulation, measured in accordance with an
embodiment of the present invention. A rat tMCAO model of stroke
was used to evaluate the benefits, including neuromuscular,
motility, cognitive, somatosensory, somatomotor, infarct volume
benefits, of rehabilitative SPG stimulation using the techniques
described herein. The stimulation was applied for seven consecutive
days beginning at 24 hours after reperfusion in the tMCAO
model.
[0148] 94 male Sprague Dawley (SD) rats were divided into six
groups, as shown in Table 2:
TABLE-US-00002 TABLE 2 Hours of stimulation Group No. of rats per
day 1 - Control 18 N/A 2 - Sham 10 N/A 3 17 1 4 16 3 5 17 6 6 16
10
[0149] Prior to performance of any surgical procedure on the rats,
the rats were trained using a series of behavior tests. Five
parameter categories were evaluated using one or more tests, as
follows: [0150] Neuromuscular function--rotarod motor test, mNSS
test, beam walking and balance test, stepping test, and staircase
skilled reaching test; [0151] Motility--open field test; [0152]
Learning memory (cognitive) water maze test; [0153] Somatosensory
sensation--adhesive removal test; and [0154] Somatomotor
sensation--corner turn test.
[0155] Transient MCAO (tMCAO) was performed on the right hemisphere
of all of rats except those of the sham group, using the techniques
described hereinabove with reference to FIGS. 11A-C. Three hours
after the occlusion, reperfusion was allowed in all groups. On the
day of tMCAO, the rats were anesthetized, and a bipolar electrode
was implanted in contact with the SPG ipsilateral to the pMCAO
(i.e., the right SPG), and connected to a controller. At 24 hours
post-tMCAO (just prior to stimulation), the rats were subjected to
neuroscoring using the mNSS scale, which has a score range of 0-18,
where 0 represents normal and 18 represents maximum neurological
defect. Rats scoring less than or equal to 9 were excluded from the
experiment.
[0156] SPG stimulation was applied for seven consecutive days
beginning at 24 hours post-tMCAO, using the following regime: a
duty cycle of 60 seconds on/12 seconds off, with two cycles every
15 minutes, at 2 mA and 10 Hz, with a 500 .mu.sec pulse width. The
stimulation was applied for fifteen minutes every 60 minutes. The
number of hours of stimulation per day was as shown in Table 2
above.
[0157] In order to assess rehabilitation, on days 8, 14, and 35
post-tMCAO, (with limited exceptions for specific tests), the rats
were subjected to the same pre-procedure behavior tests used in the
training, as described hereinabove. One day after the last behavior
testing, the rats were sacrificed and perfused. Their brains were
harvested, infarct volume was measured, and neurons were
counted.
[0158] The results of the experiment included the following: [0159]
Mortality in the SPG-stimulated groups was lower than in the
non-stimulated control group. [0160] SPG stimulation generally
improved neuromuscular functions (rotarod, mNSS, beam walk and
balance, stepping and staircase tests) in comparison to the
non-stimulated control group. [0161] SPG stimulation improved
cognitive capabilities (water maze test) in comparison to the
non-stimulated control group. [0162] There was a trend towards
increased motility (open field test) in the SPG-stimulated groups.
[0163] Somatosensory sensations were enhanced in the SPG-stimulated
groups in comparison to the non-stimulated control group. [0164]
Somatomotor competence was superior in the SPG-stimulated groups
than in the non-stimulated control groups. [0165] SPG stimulation
resulted in higher neurons counts in cortical layer V of the
ipsilateral stimulated side in comparison to the non-stimulated
control group.
[0166] In summary, in the present experiment, SPG stimulation
initiated 24 hours after tMCAO had advantageous results for all
five parameter groups evaluated. In addition, SPG stimulation
increased the number of neurons in all regions counted.
[0167] FIG. 2A is a graph showing neuroscores (mNSS test) of all
six groups, measured at 24 hours, 8 days, 14 days, and 35 days
after tMCAO, measured in accordance with an embodiment of the
present invention. As can be seen in the graph, mNSS scores of the
SPG-stimulated rats decreased in a time-dependent manner
post-tMCAO, indicating the occurrence of an active restorative,
rehabilitative process. SPG stimulation markedly and significantly
(p<0.05) improved neurological function measured at days 8, 14,
and 35 in all SPG-stimulated groups.
[0168] FIG. 2B is a graph showing the results of the stepping test
performed on the left foreleg in all six groups, measured pre-tMCAO
and at 8 days, 14 days, and 35 days after tMCAO, measured in
accordance with an embodiment of the present invention. As can be
seen in the graph, there was a significant (p<0.05) increase in
left (impaired) foreleg stepping in all SPG-stimulated rats in
comparison to the non-stimulated control group (with the exception
of the 10-hour stimulated group at day 35). Maximum improvement was
evident in the 3- and 6-hour stimulation groups at days 14 and 35,
respectively.
[0169] FIGS. 2C-F are graphs showing the results of the Morris
water maze (WM) task, measured in accordance with an embodiment of
the present invention. The Morris WM task is a standard test of
learning in which the animal repeatedly searches for a rest
platform hidden beneath the surface in a pool. The test is
especially sensitive to hippocampal and cortical damage, and
reflects attention, memory, and learning strategy. The Morris WM
task was performed on days 14 and 35 following tMCAO.
[0170] FIG. 2C is a graph showing the latency to the first
occurrence in the Old Zone (as described below) in first and second
trials at 14 days after tMCAO, measured in accordance with an
embodiment of the present invention.
[0171] This parameter assesses the rats' functional memory. The
rest platform was moved from the Old Zone (its position during
training) to the New Zone (its position during testing), and the
rats were expected to seek the Old Zone. The first trial showed
that the SPG-stimulated rats (3-, 6-, and 10-hour stimulation)
returned to the Old Zone significantly (p<0.05) more quickly
than the non-stimulated rats in the control group. The second trial
showed, although non-significantly, that the SPG-stimulated rats
returned to the Old Zone faster than the non-stimulated controls,
even though introduced to the New Zone rest platform in the first
trial. The second trial thus confirmed that the SPG-stimulated rats
showed enhanced remnants of functional memory.
[0172] FIG. 2D is a graph showing time spent in the Old Zone at day
14 after tMCAO, measured in accordance with an embodiment of the
present invention. This parameter also assesses the rats'
functional memory. As can be seen in the graph, the 3-, 6-, and
10-hour SPG-stimulated groups spent significantly (p<0.05) more
time seeking the rest platform in the Old Zone in comparison to the
non-stimulated control group.
[0173] FIG. 2E is a graph showing the latency to the first
occurrence in the New Zone in first and second trials at day 35
after tMCAO, measured in accordance with an embodiment of the
present invention. This parameter also assessed the rats'
functional memory. In the first trial, the 3-, 6-, and 10-hour
SPG-stimulated groups demonstrated superior, although
non-significant, results in finding the New Zone, compared with the
non-stimulated control group. In the second trial, all of the
SPG-stimulated groups achieved better results than the
non-stimulated control group. These results were significant
(p<0.05) only in the 3-hour stimulated group.
[0174] FIG. 2F is a graph showing the distance moved to find the
rest platform in the New Zone in first and second trials at day 35
after tMCAO, measured in accordance with an embodiment of the
present invention. This parameter assessed the rats' long-term
learning capability. In both trials the SPG-stimulated rats
demonstrated better performance than the control group. These
results were significant (p<0.05) only in the 3-hour stimulated
group during the first trial.
[0175] The staircase test (results not shown) was performed to
assess the rehabilitation of foreleg fine motorics. At day 14 after
tMCAO the SPG-stimulated groups demonstrated better performance in
the left impaired foreleg than the control group (1-, 3-, and
6-hour stimulation, significant (p<0.05) in the 3- and 6-hour
stimulated rats only). At day 35 after tMCAO the SPG-stimulated
groups demonstrated better performance in the left impaired
foreleg, significant (p<0.05) in the 3-hour stimulated rats
only.
[0176] The rotarod test (results not shown) was performed to assess
the rats' ability to remain on a rotating rod. It requires a high
degree of sensorimotor coordination and is sensitive to damage in
the basal ganglia and the cerebellum. The only significant
(p<0.05) results were in the 3-hour stimulated rats on the 35
day assessment, which remained on the rotarod significantly longer
than the control group.
[0177] FIG. 2G is a graph showing the time required for the rats to
remove an adhesive patch from the left foreleg, measured in
accordance with an embodiment of the present invention. This test
assessed both cutaneous sensitivity and sensor motor integration,
and is analogous to human neurological tests used clinically in
stroke patients. In the left impaired foreleg, the SPG-stimulated
rats showed better results than the non-stimulated controls at all
assessment days (8, 14, and 35 days). These results were
significant (p<0.05) at all three assessment days in the 3- and
6-hour stimulated groups only.
[0178] The corner test (results not shown) was performed to
evaluate the rats' tendency to favor a turn in the direction of the
ipsilateral side of the tMCAO (i.e., the right side in the
experiment). On all three assessment days (8, 14, and 35 days), all
SPG-stimulated groups showed a decrease in right side turns in
comparison to the non-stimulated control group. This decrease was
significant (p<0.05) only on day 35 in the 1- and 6-hour
stimulated rats.
[0179] The beam walk test (results not shown) was performed to
evaluate sensor motor integration, specifically hind limb function.
In general, all SPG-stimulated groups showed improved results in
comparison to the non-stimulated control group. These results were
significant (p<0.05) only on day 35 only in the 3-hour
stimulated group.
[0180] The beam balance test (results not shown) was performed to
assess gross vestibulomotor function, by requiring the rats to
balance steadily on a narrow beam. This test is sensitive to motor
cortical insults. On all assessment days (days 8, 14, and 35), all
of the SPG-stimulated groups (except the 1-hour stimulated group on
day 8) performed better than the non-stimulated control group.
These results were significant (p<0.05) only on day 14 in the
3-hour stimulated group.
[0181] The open field test (results not shown) was performed to
assess the following four parameters indicative of hippocampal and
basal ganglia damage, as well as hind limb dysfunction: [0182]
Total distance moved, which decreases in cerebrally-insulted
animals. All of the SPG-stimulated groups achieved enhanced
movement compared to the control group on day 14 after tMCAO. These
results were significant (p<0.05) only in the 3- and 6-hour
stimulated groups. [0183] Velocity, which is diminished in
cerebrally-insulted animals. All of the SPG-stimulated groups
achieved enhanced velocity compared to the control group on day 14
after tMCAO. These results were significant (p<0.05) only in the
3- and 6-hour stimulated groups. [0184] Latency of first occurrence
in center zone. All of SPG-stimulated groups (except the 10-hour
stimulated group on day 14) showed quicker entry into the center
zone in comparison to the non-stimulated control group. These
results were significant (p<0.05) only on day 35 in the 1- and
3-hour stimulated groups. [0185] Total distance moved in center
zone. On day 14, the 3- and 10-hour stimulated groups achieved
significantly (p<0.05) greater distance moved than the control
group.
[0186] FIG. 2H is a graph showing the number of neurons in cortical
layer V and II-III, measured in accordance with an embodiment of
the present invention. Neuron counting was performed in cortical
layers V and II-III in the non-stimulated control group and in the
3- and 6-hour SPG-stimulated groups. The number of neurons in
cortical layer V was significantly (p<0.05) greater in both of
these SPG-stimulated groups compared to the non-stimulated group.
In cortical layers II-III there was no significant difference
between the stimulated and non-stimulated groups.
[0187] There were no significant differences in body weigh between
the SPG-stimulated groups and the non-stimulated control group.
Metabolic Improvement
[0188] In an embodiment of the present invention, system 20 is used
to apply excitatory electrical stimulation to the SPG or another
MTS to a subject who suffers from an adverse cerebral condition, in
order to improve a metabolic state of a brain area affected by the
adverse cerebral condition, thereby improving recovery from the
condition. For some applications, the adverse cerebral condition is
a cerebrovascular infarction (stroke), and the stimulation augments
the recovery of the metabolic state of the brain area in the
infarction or a vicinity of the infarction. The inventors
hypothesize that such stimulation may improve the metabolic state
by increasing blood perfusion to the damaged tissue, which improves
the supply of oxygen and other nutrients to the tissue, and/or
increases washout of toxic waste products from the damaged tissue.
For example, lactate is a toxic waste product which, in high
concentrations, leads to acidosis of the tissue.
[0189] A method for applying such stimulation comprises identifying
an electrical stimulation protocol as being suitable for improving
a metabolic state of a brain area of a subject, and improving the
metabolic state by applying the stimulation protocol to the SPG or
another MTS. Typically, the method comprises identifying that the
subject suffers from an adverse cerebral condition, and the
metabolic state is improved responsively to identifying that the
subject suffers from the adverse cerebral condition. For some
applications, the method comprises identifying that the subject may
benefit from the improved metabolic state, and the metabolic state
is improved responsively to identifying that the subject may
benefit from the improved metabolic state.
[0190] In an embodiment of the present invention, application of
the stimulation commences at least 18 hours after an occurrence of
the infarction. Experimental results obtained by the inventors
support the efficacy of stimulation commencing 24 hours after
stroke, as described hereinbelow with reference to FIGS. 3-8B.
[0191] For some applications, the brain area is an ischemic core of
the infarction. The stimulation improves metabolism even the core,
in which cells have a high likelihood of having died during the
infarction. For some applications, identifying the stimulation
protocol comprises identifying the stimulation protocol as suitable
for reviving at least a portion of the ischemic core. Alternatively
or additionally, the brain area is the periphery around the
ischemic core.
[0192] In an embodiment of the present invention, electrical
stimulation of the SPG or another MTS reduces lactate levels in the
acute phase of a cerebrovascular infarction, or during another
adverse cerebral condition. Such a reduction in lactate levels
results in a better metabolic state for the surviving cells. As
described hereinbelow with reference to FIGS. 7A-B and 8A-B,
preliminary experimental results in a rat model indicate the SPG
stimulation reduces such lactate levels in the acute phase of the
infarction. For some applications, identifying the stimulation
protocol in the stimulation method comprises identifying the
stimulation protocol as suitable for enhancing clearance of lactate
from the brain area.
[0193] In an embodiment of the present invention, stimulation of
the SPG or another MTS augments the recovery of the metabolic state
of an infarcted brain area, which leads to a better prognosis for
acute stroke patients. Alternatively, such stimulation augments the
recovery of the metabolic state of a brain area affected by another
adverse cerebral condition, such as chronic cerebral hypoperfusion
states (such as occur in vascular dementia and Alzheimer's
disease), neurodegenerative disorders (such as Parkinson's
disease), and electrical hyperactivity states (such as epilepsy
where there is a higher metabolic demand in the affected brain
areas).
[0194] In an embodiment of the present invention, a method is
provided for improving a metabolic state of the brain in a subject
who has not been diagnosed with any neurological condition
associated with a reduced level of brain metabolism. The method
comprises identifying that the subject may benefit from an improved
metabolic state, and, responsively to identifying, applying
chronic, long-term stimulation to an MTS, such as the SPG. The
chronic stimulation has a duration of at least two weeks, at least
four weeks, at least three months, at least six months, or the
remaining life of the subject. During this chronic treatment,
stimulation is typically applied intermittently, such as during one
session per day, or less frequently, such as depending on the
severity of assessed risk. Alternatively, the stimulation is
applied generally constantly, typically at a low strength.
Metabolic State Experimental Results
[0195] Reference is made to FIGS. 3-6, which are bar graphs showing
experimental results obtained during a rat experiment performed in
accordance with an embodiment of the present invention. The
inventors conducted this experiment to assess the ability of SPG
stimulation to augment stroke recovery in MCAO rats.
[0196] Transient middle cerebral artery occlusion (t-MCAO) was
induced in twenty Wistar rats. 7 of the rats served as a control
group, and the remaining 6 rats were treated with SPG stimulation
beginning 18.+-.2 hours post-MCAO. Longitudinal .sup.1H magnetic
resonance spectroscopic imaging (.sup.1HMRSI) and diffusion MRI
(DWI) were used to evaluate ischemic brain condition of the
stimulated and control rats at 16.+-.2 h, 8 days, and 28 days
post-MCAO. In addition, the two groups were evaluated by modified
neurological severity score (mNSS). N-Acetyl-Aspartate (NAA)
levels, as obtained from .sup.1HMRSI, and a damage index, computed
from ADC maps, were used to determine the pathophysiological state
of the control and SPG-treated groups.
[0197] As described in detail below, the inventors found that
levels of NAA, which is considered to be a marker for neuronal
density and viability levels, in the stimulated and control rats
were the same 16.+-.2 hours post-MCAO (0.52.+-.0.03, 0.54.+-.0.03).
28 days post-MCAO, NAA levels were significantly higher in the
stimulated group (0.60.+-.0.04) compared to the control group
(0.50.+-.0.04) (P<0.05). This effect was more pronounced for
regions with low initial NAA values; in these regions, NAA
increased from 0.16.+-.0.03 to 0.32.+-.0.03 in the stimulated group
(P=0.04), and from 0.16.+-.0.03 to 0.10.+-.0.03 (P=0.20) in the
control group. The inventors believe that regions with the lowest
initial NAA values generally correspond to the ischemic core of the
infarction, and that regions with intermediary initial NAA values
generally correspond to the ischemic penumbra. In addition, the
damage index, calculated based on DWI, showed significant
deterioration for the controls which was not observed for the
stimulated animals.
[0198] NAA recovery after cerebral ischemia has been discussed
previously in the literature (see, for example, the above-mentioned
articles by Weber R et al. and Sager T N et al.). In the
above-mentioned article by Moffett J R et al., the following
possible contributions for this observation were suggested: (i)
surviving neuronal cells in the infarction area renew their ability
to synthesize NAA, (ii) different cells begin to express NAA, (iii)
production of NAA from N-Acetylaspartylglutamate (NAAG) by glial
cells present in the infarction core, and (iv) neurogenesis
following the ischemic event. Based on the experimental results
described herein, the inventors hypothesize that the increase in
the NAA levels in the stimulated group compared to the control
group is due to renewal of the NAA synthesis by surviving neuronal
cells. Because electrical stimulation of the SPG increases CBF in
the infarction region, and NAA synthesis is dependent on the energy
level in cells, such synthesis is reduced immediately after the
ischemic event and the depletion of energy storage. Therefore, the
increase in NAA levels in the damaged area may be caused by the
increase in the energy supply to these areas, as a result of the
increase in CBF caused by electrical stimulation of the SPG. In
contrast, as reported in the above-mentioned article by Franke C et
al., no NAA recovery had been found after tPA treatment.
[0199] The twenty Wistar rats were male, and weighed 290.+-.10 g.
The rats were anesthetized with isoflurane (4% for induction, 2%
for surgery) and ventilated with N.sub.2O:O.sub.2 (70:30%) mixture.
24 hours prior to the MCAO procedure, the head skin of the rat was
clipped and cut along the midline (cranio-caudal axis). The skin
and the orbital structures of the right side (ipsilateral to
subsequent t-MCAO) were retracted laterally to expose the ethmoidal
foramen and the ethmoidal nerve (i.e., the postganglionic
parasympathetic nerve fibers from the SPG). A hook stimulating
electrode, which was subsequently used to generate the electrical
pulses, was hooked onto the exposed fibers. The wire of the
electrode was glued onto the skull, and the receiver was placed
under the skin on the nape of the animal. The surgical wound was
closed above the right orbit. Rats of both the stimulated group and
the control group were implanted.
[0200] Prior to the t-MCAO procedure, the rats were again
anesthetized with isoflurane (4% for induction, 2% for surgery) and
ventilated with N.sub.2O:O.sub.2 (70:30%) mixture. t-MCAO was
induced by intraluminal suture occlusion of the right MCA, using
the suture model as described by Spratt N J et al., "Modification
of the method of thread manufacture improves stroke induction rate
and reduces mortality after thread-occlusion of the middle cerebral
artery in young or aged rats," J Neurosci Methods 2006;
155:285-290, which is incorporated herein by reference. In brief,
4-0 monofilament nylon suture (SMI, Belgium) was coated with
silicon (Wacker-Chemie, Germany) and inserted through the proximal
external carotid artery into the internal carotid artery and then
into the circle of Willis, effectively occluding the MCA. The
suture was placed for two hours and subsequently removed. The
surgical wound was closed and the animals returned to their cages
for a recovery period of approximately sixteen hours.
[0201] Arterial blood samples were taken before, and immediately
after the MCAO, to measure pH, PaO.sub.2 and PaCO.sub.2. Body
temperature was maintained at 37.0.+-.0.5.degree. C., using an
electrical heating pad. Five rats died during the first sixteen
hours, prior to the MR experiment. Six rats were stimulated. Two of
nine rats in the control group died within the first week.
[0202] Magnetic resonance imaging (MRI) and spectroscopy (MRS) are
widely used for investigating, in vivo, neurological disorders in
general, and ischemic stroke in particular. The versatility of the
MR technique enables non-invasive studying of not only the
progression of neurological pathology during longitudinal
follow-up, but also the evaluation of the pathophysiological state
of the studied tissue, without the need of animal sacrificing. Of
the available MR approaches, diffusion weighted imaging (DWI) is a
powerful tool for early stroke detection. DWI enables observation
of ischemic tissues within minutes following the ischemic event.
Apparent diffusion coefficient (ADC) maps, calculated from DWI, may
be used to evaluate infarction size as well as tissue condition,
and correlate to infarction sizes evaluated from histology. The
acute stage of the ischemic stroke is characterized, inter alia, by
cellular swelling (cytotoxic edema) and increase in the
extracellular tortuosity that reduces the ADC of the water
molecules in the ischemic region. In the chronic stage of ischemic
stroke, high ADC values (compared to the contralateral regions) are
observed for the infarction area as a result of the necrotic
process that includes cells death and membrane loss. Therefore, ADC
values computed at the chronic stage and normalized to the
contralateral hemisphere values can predict tissue condition.
Simultaneously with the changes in the diffusion characteristics of
water within the ischemic region, changes in levels of different
brain metabolites can be detected by different MRS methodologies.
Of these metabolites, N-acetyl-aspartate (NAA) is considered to be
a marker for neuronal density and viability, affording information
about the neuronal tissue condition and it may predict the brain
status at the chronic stage (see, for example, the two
above-mentioned articles by Demougeot C et al.).
[0203] The MR experiments were performed using a 7T/30 cm BioSpec
system (Bruker, Germany) equipped with a BGU20 gradient system,
capable of producing pulse gradients of 400 mT/m in each of the
three dimensions. A transmit body coil (ID=150 mm) and a receive
surface coil (ID=15 mm) actively decoupled were used to acquire MRI
and MRS data. Control (n=7) and treated (n=6) rats were examined by
MRS and MRI under isoflurane anesthesia (induction 4.0%,
maintenance 1.5%) in N.sub.2O:O.sub.2 gas mixture. Each rat was
examined at three time points: 16.+-.2 h, 8 days and 28 days
post-t-MCAO.
[0204] T2 weighted MRI images (T.sub.2WI) were collected using the
RARE sequence (RARE factor=8) with the following parameters: field
of view (FOV) of 25.6.times.25.6 mm.sup.2 and 256.times.128 digital
resolution reconstructed to 256.times.256. Eight continuous 2 mm
slices were collected, using TR/TE of 3000/75 ms with four averages
in 3 minutes and 45 seconds. ADC maps were calculated from two
spin-echo four-shot echo planar images (EPI), collected with and
without diffusion sensitizing gradient pulses and with the
following parameters: .delta.=4.5 ms, .DELTA.=40 ms and G=173 mT/m,
resulting in a b.sub.max of 1500 s/mm.sup.2. The same geometry
(i.e., slices and FOV) used in T.sub.2WI was used in the DWI
protocol. For diffusion images, the matrix was 96.times.96
reconstructed to 128.times.128 with TR/TE=2000/53 ms. The entire
DWI protocol was completed within two minutes.
[0205] 2 mm slice-selected two-dimensional (2D) .sup.1H-MRSI was
performed with the following parameters: FOV of 25.6.times.25.6
mm.sup.2 with VAPOR water suppression, a matrix of 8.times.8
reconstructed to 16.times.16, resulting in 256 voxels of
1.6.times.1.6.times.2.0 mm.sup.3. TR/TE=2000/135 ms were used with
32 averages. The total collection time of the .sup.1H-MRSI data was
47 minutes.
[0206] After the completion of the first MR protocol (16.+-.2 hours
post-t-MCAO) the SPG-stimulated rats (treated group) were moved to
a dedicated RF activation cage (BrainsGate, Israel) which enables
wireless stimulation. The following electrical stimulation protocol
was applied: two 60-second long pulses separated by 12 seconds of
off-time, applied every 15 minutes (8 pulses per hour). Each pulse
was of 2 mA amplitude, 0.5 ms pulse width and 10 Hz frequency. SPG
stimulation started 18.+-.2 hours post-t-MCAO surgery and was
applied for 3 hours, for seven consecutive days.
[0207] 2D .sup.1H-MRSI raw data were split into 256 individual NMR
spectra. 15 spectra from the ipsilateral hemisphere and their
respective contralateral spectra were used to calculate normalized
total-NAA values for each examined animal at all three time points,
i.e., at 16.+-.2 h, 8 days, 28 days post t-MCAO. NAA integration
values were determined by using the line fitting procedure of
MestRe-C software (Mestrelab Research, Santiago de Compostela,
Spain). The NAA integration values of the ipsilateral voxels were
normalized to the NAA values obtained for the contralateral voxels,
to determine the normalized level of the NAA in the ischemic side
compared to the non-ischemic side.
[0208] ADC maps were calculated from two contiguous EPI diffusion
experiments with b-values of 1.5 and 1500 s/mm.sup.2. Lesion
volumes were calculated, blindly, for all slices, by manually
choosing the area of DWI abnormality in each slice and multiplying
it by the slice thickness. 16.+-.2 hours post-t-MCAO, regions
having lower ADC values compared to the contralateral hemisphere
were analyzed. 28 days post-t-MCAO, regions with higher ADC values
compared to the contralateral hemisphere values were chosen for the
lesion volumes calculation.
[0209] The damage index was calculated from the ADC maps at the
first and last time points. First, the normalized lesion values
(NLVs) were calculated by dividing the average ADC value in the
lesion area by the average ADC value of its respective
contralateral region of interest (ROI):
N L V = AverageLesionValue AverageContraLateralValue ( Equation 1 )
##EQU00001##
[0210] Since the ADC values of the lesion area obtained 16.+-.2
hours after the stroke were smaller than those of the contralateral
ROI, the damage index was calculated using the following
equation:
DI(16 h)=(1-NLV).times.LV (Equation 2)
[0211] Such a calculation enables evaluation of the injured tissue
condition relative to the normal contralateral tissue. As expected,
28 days post-t-MCAO, the ADC values of the lesion area were higher
compared to those observed in the contralateral ROI. In this case
the damage index was calculated using the following equation:
DI(1 month)=(NLV-1).times.LV (Equation 3)
[0212] Total lesion volume and total damage index were calculated
by accumulating all legion volumes and damage indices,
respectively, obtained for each animal 16.+-.2 hours post t-MCAO
and 28 days post-t-MCAO.
[0213] A neurological modified Neuro Severity Score (mNSS) test,
scale 0-18, was performed at the three time points: (1) 16.+-.2
hours post-t-MCAO (before the first stimulation of the treated
group), (2) 8 days and (3) 28 days post occlusion.
[0214] The results were analyzed by two-tails Student's t-Test.
P<0.05 was considered significant.
[0215] All rats involved in the experiment had normal physiological
parameters, i.e., pH, PO.sub.2, PCO.sub.2 and temperature
(maintained at 37.5.degree. C. by electrical heating pad), before,
during and after occlusion.
[0216] FIG. 3 shows the changes in the total normalized NAA values
determined from .sup.1H-MRSI for the three experimental time points
post-t-MCAO. As can be seen in the figure, there was a significant
difference between the normalized NAA values of the two groups at
the end of the study (day 28), whereas such a difference was not
observed at the first time point, i.e., 16.+-.2 hours post-t-MCAO.
The stimulated and control groups started from similar averaged
values of total normalized NAA values of 0.52.+-.0.03 and
0.54.+-.0.03, respectively (P=0.7), and reached different averaged
normalized NAA values of 0.60.+-.0.04 and 0.50.+-.0.04,
respectively, 28 days post-t-MCAO (P<0.05).
[0217] To obtain more specific information from the MRS data, the
normalized NAA values in the ischemic hemisphere at 16.+-.2 hours
post t-MCAO were classified into three categories: (a) voxels with
normalized NAA values greater than 0.7, (b) voxels with
normalized-NAA values between 0.4 and 0.7, and (c) voxels with
normalized NAA values less than 0.4.
[0218] FIGS. 4A-C show summarized changes in the NAA values of
these categories, respectively. FIG. 4A shows that there were no
significant differences between SPG-stimulated and control groups
at all three time points for voxels with normalized NAA values
greater than 0.7.
[0219] FIG. 4B shows that in the voxels having initial
normalized-NAA values between 0.4 and 0.7, there was an increase in
normalized NAA values in the SPG-stimulated group compared to the
control group, in which such an improvement in the normalized NAA
was not observed. For these voxels, the normalized-NAA values of
the SPG-stimulated group increased from 0.54.+-.0.02 (16.+-.2
hours) to 0.64.+-.0.05 (day 8) and to 0.69.+-.0.04 (day 28), while
those of the rats in the control group did not change significantly
(from 0.57.+-.0.04 at 16.+-.2 hours to 0.59.+-.0.05 28 days post
t-MCAO).
[0220] FIG. 4C shows that the greatest response to treatment was
obtained in the voxels in which normalized NAA values were less
than 0.4 at 16.+-.2 hours post occlusion. These voxels, which
showed the most dramatic reduction in NAA levels 16.+-.2 hours
post-occlusion, also exhibited the most dramatic response to
treatment. For these voxels, the control group showed a decrease in
the normalized NAA levels with time, from 0.16.+-.0.03 at 16.+-.2
hours to 0.10.+-.0.03 28 days post-occlusion, whereas the treated
group showed the opposite trend. In the SPG-stimulated animals, NAA
levels from these voxels significantly improved from 0.16.+-.0.03
at 16.+-.2 hours to 0.32.+-.0.03 28 days post MCAO (P=0.01). For
these voxels, although the control and SPG-stimulated groups had
had the same initial NAA values at 16.+-.2 hours post occlusion
(0.16.+-.0.03, P=0.97), at 28 days post occlusion a dramatic
difference in the normalized NAA values of the SPG-stimulated
animals (0.32.+-.0.07) and the controls (0.10.+-.0.03, P=0.007) was
found.
[0221] FIG. 5 shows the damage index for the two groups as computed
from the diffusion MRI 16.+-.2 hours and 28 days post t-MCAO. The
damage index was not calculated for the day 8 time point, because
of pseudo-normalization that may occur at this time point. As can
be seen in the figure, both groups began with the same damage index
values (28.+-.18 for the SPG-stimulated animals and 28.+-.15 for
the control rats, P=0.98). The DWI data show that less
deterioration in the damage index occurred in the SPG-stimulated
group than in the control group. For the SPG-treated animals, the
calculated damage indices did not change significantly in the day
28 follow up (P=0.15). However, the deterioration in the damage
indices of the untreated animals was statistically significant
(P=0.03).
[0222] FIG. 6 shows the average mNSS values obtained for the two
studied groups, at all three experimental time points. Both groups
began with approximately the same neuronal score, with mNSS values
of 8.5.+-.1.0 (for the SPG-stimulated group) and 8.3.+-.0.8 (for
the control group, P=0.86). Eight days post-t-MCAO, a significant
difference in the mNSS of the two groups (5.6.+-.0.8 for the
control rats and 3.8.+-.0.4 for the SPG-treated animals, P=0.04)
was found. 28 days post-t-MCAO, the difference in the mNSS between
the groups was maintained (4.3.+-.0.9 versus 2.3.+-.0.5) but
somewhat less significant (P=0.08).
[0223] Reference is made to FIGS. 7A-B and 8A-B, which show
magnetic resonance spectra obtained during an experiment conducted
by the inventors, measured in accordance with an embodiment of the
present invention. The inventors conducted this experiment to
assess the ability of SPG stimulation to reduce lactate levels in
MCAO rats.
[0224] Transient middle cerebral artery occlusion (t-MCAO) was
induced in 4 Wistar rats, using the technique described hereinabove
with reference to FIGS. 2-5. 2 of the rats served as a control
group, and the remaining 2 rats were treated with SPG stimulation
beginning 24 hours post-MCAO. Longitudinal .sup.1H magnetic
resonance spectroscopic imaging (.sup.1HMRSI) was used to evaluate
lactate levels at 20 hours post-MCAO (prior to SPG stimulation) and
at 27 hours (immediately after the completion of SPG stimulation in
the treated group). 2 mm slice-selected .sup.1H-MRSI was performed
using a 7T/30 cm Biospec system (Bruker, Germany) equipped with a
BGU20 gradient system, capable of producing pulse gradients of 400
mT/m in each of the three dimensions, with the following
parameters: FOV of 25.6.times.25.6 mm.sup.2 with VAPOR water
suppression, one voxel -3.times.3.times.3 mm (dimensions)
TR/TE=3500/135 ms, NA=128, DS=8, exposure time}=8 minutes. Spectral
lines were determined by taking an average over the whole voxel.
.sup.1H-MRSI measurements were taken in each session from four
different locations: [0225] 1) the ipsilateral ischemic core, as
defined defined by the T2 image; [0226] 2) the same area as the
ischemic core, but on the contralateral side; [0227] 3) the
ipsilateral ischemic penumbra, as defined defined by the T2 image;
and [0228] 4) the same area as the ischemic penumbra, but on the
contralateral side.
[0229] After the completion of the first MR protocol (20 hours
post-MCAO) the SPG-stimulated rats (treated group) were moved to a
dedicated RF activation cage (BrainsGate, Israel) which enables
wireless stimulation. The following electrical stimulation protocol
was applied: two 60-second long pulses separated by 12 seconds of
off-time, applied every 15 minutes (8 pulses per hour). Each pulse
was of 2 mA amplitude, 0.5 ms pulse width and 10 Hz frequency. SPG
stimulation started 24 hours after t-MCAO surgery and was applied
for 3 hours, during a single stimulation session.
[0230] .sup.1H-MRSI raw data respective contralateral spectra were
used to calculate normalized total-LAC values for each examined
animal at two time points, at 20 hours post-t-MCAO and immediately
post-t-MCAO. Lactate integration values were determined by using
the line fitting procedure of MestRe-C software (Mestrelab
Research, Santiago de Compostela, Spain). The lactate integration
values of the ipsilateral voxels were normalized to the lactate
values obtained for the contralateral voxels, to determine a
normalized level of lactate in the ischemic side compared to the
non-ischemic side.
[0231] FIGS. 7A and 7B show magnetic resonance spectra of an
infarction core before and after SPG stimulation, respectively,
measured in accordance with an embodiment of the present invention.
As described above, spectra were also measured for the
contralateral side (not shown). The average normalized lactate
levels at the ipsilateral core were 62 prior to SPG stimulation,
and 54 after three hours of SPG stimulation, representing a 12.5%
reduction in lactate level. This reduction is reflected by a
reduction of the negative lactate peak shown in the figures.
[0232] FIGS. 8A and 8B show magnetic resonance spectra of an
infarction penumbra before and after SPG stimulation, respectively,
measured in accordance with an embodiment of the present invention.
As described above, spectra were also measured for the
contralateral side (not shown). The average normalized lactate
levels at the ipsilateral penumbra were 46 prior to SPG
stimulation, and 40 after three hours of SPG stimulation,
representing a 15% reduction in lactate level. This reduction is
reflected by a reduction of the negative lactate peak shown in the
figures.
[0233] The inventors hypothesize that these observed reductions in
lactate levels were caused by the partial transition from anaerobic
respiration to aerobic respiration as the metabolic state of the
damaged cells improved because of the applied SPG stimulation,
because of a higher efflux of lactate from the ischemic tissue, or
from a combination of these two mechanisms.
[0234] In an embodiment of the present invention, the stimulation
described hereinabove (for augmenting cell genesis, or for
improving metabolic state) is applied on a chronic, long-term
basis, i.e., for at least one week, such as at least two weeks, at
least four weeks, at least three months, at least six months, or
longer, such as for the remainder of the subject's life. During
this chronic treatment, stimulation is typically applied
intermittently, such as during one session per day, or less
frequently, such depending on the severity of assessed risk. For
some applications, each session has a duration of between 1 minute
and 6 hours, such as at least 5 minutes or at least 15 minutes, or
between 2 and 4 hours, e.g., about 3 hours or about 6 hours, or
more than 6 hours. Alternatively, the system is configured to apply
such stimulation generally constantly, i.e., 24 hours per day.
Further alternatively, the stimulation is applied less frequently
than every day, such as once every other day (e.g., at least one
minute during every 48 hours), or more frequently than once per
day, such as during two sessions per day.
[0235] For some applications, the stimulation is applied during a
plurality of stimulation periods which includes at least first and
last stimulation periods. System 20 sets an inter-period interval
between initiation of the first period and initiation of the last
period to be at least 24 hours. For example, the first stimulation
period may occur from 1:00 P.M. to 4:00 P.M. on a Monday, and the
last stimulation period may occur from 1:00 P.M. to 4:00 P.M. on a
Tuesday of the same week. Optionally, stimulation is applied during
at least one additional stimulation period between the first and
last periods. For example, stimulation may be additionally applied
from 1:00 A.M. to 4:00 A.M. on the Tuesday. For some applications,
the first period concludes simultaneously with the initiation of
the last period, i.e., the stimulation is applied constantly from
the beginning of the first period until the conclusion of the last
period. For example, the stimulation may be applied constantly from
1:00 P.M. on Monday, January 1 to 4:00 P.M. on Tuesday, January 2,
or constantly from 1:00 P.M. on Monday, January 1 to 4:00 P.M. on
Monday, January 29. Alternatively, the initiation of the last
stimulation period occurs after a conclusion of the first
stimulation period, such that the stimulation is not applied during
at least one non-stimulation period between the conclusion of the
first stimulation period and the initiation of the last stimulation
period.
[0236] For some applications, the system sets the inter-period
interval to be at least 48 hours, such as at least one week, at
least two weeks, or at least four weeks. When using such greater
inter-period intervals, the system typically, but not necessarily,
applies stimulation during at least several additional stimulation
periods between the first and last stimulation periods. For some
applications, such additional stimulation periods may include a
plurality of daily stimulation periods, applied on every day
between the initiation of the first stimulation period and the
initiation of the last stimulation period. For example, the first
stimulation period may occur from 1:00 P.M. to 4:00 P.M. on Monday,
January 1, the last stimulation period may occur from 1:00 P.M. to
4:00 P.M. on Monday, January 8, and the additional daily
stimulation periods may occur from 1:00 P.M. to 4:00 P.M. on each
day from Tuesday, January 2 through Sunday, January 7, inclusive.
For some applications, stimulation is applied for at least 30
minutes every day (e.g., at least 60 minutes every day) between the
initiation of the first stimulation period and the initiation of
the last stimulation period. For some applications, stimulation is
applied during a plurality of non-continuous stimulation periods
during each 24-hour period between the initiation of the first
stimulation period and the initiation of the last stimulation
period. For example, the first stimulation period may occur from
1:00 P.M. to 4:00 P.M. on Monday, the last stimulation period may
occur from 1:00 P.M. to 4:00 P.M. on Wednesday, and stimulation may
be applied during additional stimulation periods from (a) 1:00 A.M.
to 4:00 A.M. on Tuesday, (b) from 1:00 P.M. to 4:00 P.M. on
Tuesday, and (c) from 1:00 A.M. to 4:00 A.M. on Wednesday, such
that stimulation is applied during two stimulation periods during
the 24-hour period from 1:00 P.M. on Monday to 1:00 P.M. on
Tuesday, and during two stimulation periods during the 24-hour
period from 1:00 P.M. on Tuesday to 1:00 P.M. on Wednesday.
[0237] For some applications, the system is configured to set the
inter-period interval to be no more than a maximum value, such as
three, six, nine, or twelve months. For some applications, the
system comprises a user interface, which enables a healthcare
worker to enter a value for the inter-period interval. The system
typically rejects values that are greater than the maximum value,
such as by requiring the healthcare worker to enter another value,
or by using the maximum value instead of the entered value.
Alternatively, the system notifies the healthcare worker if the
entered value is greater than the maximum value; optionally, the
system allows the healthcare worker to override the
notification.
[0238] For some applications, the system is configured to store a
maximum total time of stimulation per each time period having a
given duration, and to apply the stimulation no more than the
maximum total time per each time period having the given duration.
For example, the given duration of each time period may be 24
hours. Typical values for the maximum total time of stimulation per
24-hour period include one hour, three hours, six hours, ten hours,
and twelve hours. For some applications, the maximum total time of
stimulation is predetermined, e.g., by the manufacturer of the
system, while for other applications, a healthcare worker enters
the maximum total time of stimulation into the system.
[0239] As used in the present application, including the claims, a
"stimulation period" includes an entire period during which
stimulation is applied, even though current is applied to the site
only during a portion of the period, because of the duty cycle,
on/off periods, and/or frequency of the current, for example.
[0240] For some applications, the stimulation is applied
bilaterally to both SPGs, while for other applications, the
stimulation is applied unilaterally to the MTS (e.g., the SPG) that
supplies the more affected hemisphere of the brain. For some
applications in which the stimulation is applied bilaterally,
techniques are used that are described in U.S. application Ser. No.
11/573,993, filed Feb. 19, 2007, entitled, "Concurrent bilateral
SPG modulation," which is assigned to the assignee of the present
application and is incorporated herein by reference.
[0241] "Strength," as used in the present application, including
the claims, means a total charge applied to an MTS in a given time
period, e.g., one minute, one hour, or one day. Strength is
increased or decreased by changing one or more parameters of the
applied stimulation, such as the amplitude, number of cycles in a
given time period, frequency, pulse width, or duty cycle (e.g.,
ratio of "on" to "off" time within a given cycle), as described
hereinbelow in greater detail.
[0242] In an embodiment of the present invention, techniques
described herein are performed in conjunction with techniques
described in U.S. Pat. No. 7,117,033, which is incorporated herein
by reference.
[0243] In an embodiment of the present invention, bipolar
stimulation is applied, in which a first electrode is applied to a
first MTS, and a second electrode is applied to a second MTS.
[0244] In some embodiments of the present invention, techniques
described herein are practiced in combination with techniques
described in one or more of the references cited in the Background
of the Invention section hereinabove and/or in combination with
techniques described in one or more of the patent applications
cited hereinabove.
[0245] The scope of the present invention includes embodiments
described in the following patent applications, which are assigned
to the assignee of the present patent application and are
incorporated herein by reference. In an embodiment of the present
invention, techniques and apparatus described in one or more of the
following applications are combined with techniques and apparatus
described herein: [0246] U.S. Provisional Patent Application
60/203,172, filed May 8, 2000, entitled, "Method and apparatus for
stimulating the sphenopalatine ganglion to modify properties of the
BBB and cerebral blood flow" [0247] U.S. patent application Ser.
No. 10/258,714, filed Oct. 25, 2002, which issued as U.S. Pat. No.
7,120,489 [0248] U.S. Provisional Patent Application 60/364,451,
filed Mar. 15, 2002, entitled, "Applications of stimulating the
sphenopalatine ganglion (SPG)" [0249] U.S. Provisional Patent
Application 60/368,657, filed Mar. 28, 2002, entitled, "SPG
Stimulation" [0250] U.S. Provisional Patent Application 60/376,048,
filed Apr. 25, 2002, entitled, "Methods and apparatus for modifying
properties of the BBB and cerebral circulation by using the
neuroexcitatory and/or neuroinhibitory effects of odorants on
nerves in the head" [0251] U.S. Provisional Patent Application
60/388,931, filed Jun. 14, 2002, entitled "Methods and systems for
management of Alzheimer's disease," PCT Patent Application
PCT/IL03/000508, filed Jun. 13, 2003, claiming priority therefrom,
and U.S. patent application Ser. No. 10/518,322 in the national
stage thereof, which published as US Patent Application Publication
2006/0020299 [0252] U.S. Provisional Patent Application 60/400,167,
filed Jul. 31, 2002, entitled, "Delivering compounds to the brain
by modifying properties of the BBB and cerebral circulation" [0253]
U.S. Provisional Patent Application 60/426,180, filed Nov. 14,
2002, entitled, "Surgical tools and techniques for sphenopalatine
ganglion stimulation," [0254] PCT Patent Application
PCT/IL03/000966, filed Nov. 13, 2003, a U.S. patent application
Ser. No. 10/535,024 in the national stage thereof, which published
as US Patent Application Publication 2006/0195169 [0255] U.S.
Provisional Patent Application 60/426,182, filed Nov. 14, 2002
[0256] PCT Patent Application PCT/IL03/000967, filed Nov. 13, 2003,
entitled, "Stimulation circuitry and control of electronic medical
device," and U.S. patent application Ser. No. 10/535,028 in the
national stage thereof [0257] U.S. patent application Ser. No.
10/294,310, filed Nov. 14, 2002, which issued as U.S. Pat. No.
7,146,209 [0258] PCT Patent Application PCT/IL03/000631, filed Jul.
31, 2003, entitled, "Delivering compounds to the brain by modifying
properties of the BBB and cerebral circulation," which published as
PCT Publication WO 04/010923, and U.S. patent application Ser. No.
10/522,615 in the national stage thereof [0259] U.S. Pat. No.
6,853,858 to Shalev [0260] U.S. patent application Ser. No.
10/783,113, filed Feb. 20, 2004, which issued as U.S. Pat. No.
7,117,033 [0261] U.S. Provisional Patent Application 60/426,181,
filed Nov. 14, 2002, entitled, "Stimulation for treating ear
pathologies," [0262] PCT Patent Application PCT/IL03/000963, filed
Nov. 13, 2003, which published as PCT Publication WO 04/045242, and
U.S. patent application Ser. No. 10/535,025 in the national stage
thereof [0263] U.S. Provisional Patent Application 60/448,807,
filed Feb. 20, 2003, entitled, "Stimulation for treating
autoimmune-related disorders of the CNS" [0264] U.S. Provisional
Patent Application 60/461,232, filed Apr. 8, 2003, entitled,
"Treating abnormal conditions of the mind and body by modifying
properties of the blood-brain barrier and cephalic blood flow"
[0265] PCT Patent Application PCT/IL03/00338, filed Apr. 25, 2003,
and U.S. patent application Ser. No. 10/512,780 in the national
stage thereof, which published as US Patent Application
2005/0266099 [0266] U.S. Provisional Patent Application 60/506,165,
filed Sep. 26, 2003, entitled, "Diagnostic applications of
stimulation" [0267] U.S. patent application Ser. No. 10/678,730,
filed Oct. 2, 2003, which published as US Patent Application
2005/0074506 [0268] PCT Patent Application PCT/IL04/000897, filed
Sep. 26, 2004, entitled, "Stimulation for treating and diagnosing
conditions," which published as PCT Publication WO 05/030025 [0269]
U.S. Provisional Patent Application 60/604,037, filed Aug. 23,
2004, entitled, "Concurrent bilateral SPG modulation" [0270] PCT
Patent Application PCT/IL05/000912, filed Aug. 23, 2005, entitled,
"Concurrent bilateral SPG modulation," which published as PCT
Publication WO 06/021957, and U.S. patent application Ser. No.
11/573,993 in the national stage thereof [0271] U.S. patent
application Ser. No. 10/952,536, filed Sep. 27, 2004, entitled,
"Stimulation for treating and diagnosing conditions," which
published as US Patent Application Publication 2005/0159790 [0272]
U.S. patent application Ser. No. 11/349,020, filed Feb. 7, 2006,
which published as US Patent Application Publication 2006/0287677
[0273] U.S. patent application Ser. No. 11/465,381, filed Aug. 17,
2006, which published as US Patent Application Publication
2007/0083245 [0274] U.S. patent application Ser. No. 11/668,305,
filed Jan. 19, 2007, which published as US Patent Application
Publication 2008/0033509 [0275] U.S. patent application Ser. No.
11/874,529, filed Oct. 18, 2007
[0276] In an embodiment of the present invention, electrical
stimulation system 20 comprises circuitry described in one or more
of the above-mentioned applications.
[0277] In an embodiment of the present invention, an MTS is
stimulated using the magnetic stimulation apparatus and methods
described in the above-mentioned U.S. patent application Ser. No.
10/783,113.
[0278] It will be appreciated by persons skilled in the art that
the present invention is not limited to what has been particularly
shown and described hereinabove. Rather, the scope of the present
invention includes both combinations and subcombinations of the
various features described hereinabove, as well as variations and
modifications thereof that are not in the prior art, which would
occur to persons skilled in the art upon reading the foregoing
description. For example, elements which are shown in a figure to
be housed within one integral unit may, for some applications, be
disposed in a plurality of distinct units. Similarly, apparatus for
communication and power transmission which are shown to be coupled
in a wireless fashion may, alternatively, be coupled in a wired
fashion, and apparatus for communication and power transmission
which are shown to be coupled in a wired fashion may,
alternatively, be coupled in a wireless fashion.
* * * * *